IMPORTANCE: Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on ...families. OBJECTIVE: To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. DESIGN, SETTING, AND PARTICIPANTS: In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. INTERVENTION: Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). MAIN OUTCOMES AND MEASURES: Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents’ relationship (Kansas Marital Satisfaction Scale), and parents’ psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). RESULTS: A total of 519 parents (275 women 53.0%; mean SD age, 35.1 4.5 years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean SE Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 0.15; 3 months, –0.18 0.18; 10 months, –0.07 0.20; joint P = .57) or parents’ psychological distress (between-group ratio of adjusted mean SE Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 0.08; 3 months, 1.07 0.11; joint P = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents’ relationship measure differed between groups over time (between-group difference in adjusted mean SE Kansas Marital Satisfaction Scale scores: postdisclosure, –0.19 0.07; 3 months, –0.04 0.07; and 10 months, –0.01 0.08; joint P = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02422511
Genetic testing for pediatric cancer predisposition syndromes (CPS) could augment newborn screening programs, but with uncertain benefits and costs.
We developed a simulation model to evaluate ...universal screening for a CPS panel. Cohorts of US newborns were simulated under universal screening versus usual care. Using data from clinical studies, ClinVar, and gnomAD, the presence of pathogenic/likely pathogenic (P/LP) variants in RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, and PHOX2B were assigned at birth. Newborns with identified variants underwent guideline surveillance. Survival benefit was modeled via reductions in advanced disease, cancer deaths, and treatment-related late mortality, assuming 100% adherence.
Among 3.7 million newborns, under usual care, 1,803 developed a CPS malignancy before age 20. With universal screening, 13.3% were identified at birth as at-risk due to P/LP variant detection and underwent surveillance, resulting in a 53.5% decrease in cancer deaths in P/LP heterozygotes and a 7.8% decrease among the entire cohort before age 20. Given a test cost of $55, universal screening cost $244,860 per life-year gained; with a $20 test, the cost fell to $99,430 per life-year gained.
Population-based genetic testing of newborns may reduce mortality associated with pediatric cancers and could be cost-effective as sequencing costs decline.
Over 100 million research participants around the world have had research array-based genotyping (GT) or genome sequencing (GS), but only a small fraction of these have been offered return of ...actionable genomic findings (gRoR). Between 2017 and 2021, we analyzed genomic results from 36,417 participants in the Mass General Brigham Biobank and offered to confirm and return pathogenic and likely pathogenic variants (PLPVs) in 59 genes. Variant verification prior to participant recontact revealed that GT falsely identified PLPVs in 44.9% of samples, and GT failed to identify 72.0% of PLPVs detected in a subset of samples that were also sequenced. GT and GS detected verified PLPVs in 1% and 2.5% of the cohort, respectively. Of 256 participants who were alerted that they carried actionable PLPVs, 37.5% actively or passively declined further disclosure. 76.3% of those carrying PLPVs were unaware that they were carrying the variant, and over half of those met published professional criteria for genetic testing but had never been tested. This gRoR protocol cost approximately $129,000 USD per year in laboratory testing and research staff support, representing $14 per participant whose DNA was analyzed or $3,224 per participant in whom a PLPV was confirmed and disclosed. These data provide logistical details around gRoR that could help other investigators planning to return genomic results.
Disease-modifying treatments for Alzheimer's disease are emerging. Our research examined how personal risk for AD may influence intentions to ask for medications to delay symptoms of AD, and how the ...availability of such medications impacts interest in AD-related genetic testing. Invitations to a web-based survey were posted on social media sites. Respondents were sequentially assigned to imagine that they had a 5%, 15%, or 35% chance of developing AD. They were then provided a hypothetical scenario describing a medication that delayed AD symptoms. After reporting intentions to ask for the medication, respondents were asked about their interest in genetic testing to predict AD risk. Data from 310 individuals were analyzed. Intentions to ask for a preventative medication were greater for respondents presented AD risks of 35% compared to risks of 15% and 5% (86% vs. 66% vs. 62%, respectively, p < 0.001). The proportion who would ask for genetic susceptibility testing increased from 58% to 79% when respondents were told to imagine that a medication that delayed AD symptoms existed (p < 0.001). Findings suggest that individuals who know they have an increased risk for AD are more likely pursue medications to delay onset of disease symptoms, and the availability of AD-delaying treatments will increase interest in associated genetic testing. Findings provide insight about who will pursue emerging preventative medications, including individuals for whom the medications may be inappropriate, and the impact on genetic test utilization.
Genetic counseling for patients who are pursuing genetic testing in the absence of a medical indication, referred to as elective genomic testing (EGT), is becoming more common. This type of testing ...has the potential to detect genetic conditions before there is a significant health impact permitting earlier management and/or treatment. Pre‐ and post‐test counseling for EGT is similar to indication‐based genetic testing. Both require a complete family and medical history when ordering a test or interpreting a result. However, EGT counseling has some special considerations including greater uncertainties around penetrance and clinical utility and a lack of published guidelines. While certain considerations in the selection of a high‐quality genetic testing laboratory are universal, there are some considerations that are unique to the selection of a laboratory performing EGT. This practice resource intends to provide guidance for genetic counselors and other healthcare providers caring for adults seeking pre‐ or post‐test counseling for EGT. Genetic counselors and other genetics trained healthcare providers are the ideal medical professionals to supply accurate information to individuals seeking counseling about EGT enabling them to make informed decisions about testing and follow‐up.
Compared to the general population, individuals with Down syndrome (DS) are at a significantly increased risk to develop mental health conditions. This study sought to examine individuals with DS and ...co‐existing mental health comorbidities at one DS specialty clinic. Retrospective chart review of medical records including demographics, genetic testing history, personal and familial mental health history, referrals for mental health indications, and recommendations was performed. Summary statistics, logistic regression, and log of odds were converted to odd ratios to assess associations and significance. The charts of 327 patients, average 19.4 years of age (1–70), were reviewed. Nearly half the participants (42.2%) had at least one diagnosis of a mental health condition. Those with a family history were significantly more likely to have a personal diagnosis of a mental health condition than those without a family history (p < 0.01). Moreover, those who completed referrals often received medical management recommendations (86%). This study highlights the prevalence of mental health comorbidities among individuals with DS, and the referral process for mental health conditions, at one DS specialty clinic. Further research is needed to investigate our family history findings, and to determine if these results are generalizable across other DS clinics.
Polygenic risk scores (PRS), which offer information about genomic risk for common diseases, have been proposed for clinical implementation. The ways in which PRS information may influence a ...patient's health trajectory depend on how both the patient and their primary care provider (PCP) interpret and act on PRS information. We aimed to probe patient and PCP responses to PRS clinical reporting choices METHODS: Qualitative semi-structured interviews of both patients (N=25) and PCPs (N=21) exploring responses to mock PRS clinical reports of two different designs: binary and continuous representations of PRS.
Many patients did not understand the numbers representing risk, with high numeracy patients being the exception. However, all the patients still understood a key takeaway that they should ask their PCP about actions to lower their disease risk. PCPs described a diverse range of heuristics they would use to interpret and act on PRS information. Three separate use cases for PRS emerged: to aid in gray-area clinical decision-making, to encourage patients to do what PCPs think patients should be doing anyway (such as exercising regularly), and to identify previously unrecognized high-risk patients. PCPs indicated that receiving "below average risk" information could be both beneficial and potentially harmful, depending on the use case. For "increased risk" patients, PCPs were favorable towards integrating PRS information into their practice, though some would only act in the presence of evidence-based guidelines. PCPs describe the report as more than a way to convey information, viewing it as something to structure the whole interaction with the patient. Both patients and PCPs preferred the continuous over the binary representation of PRS (23/25 and 17/21, respectively). We offer recommendations for the developers of PRS to consider for PRS clinical report design in the light of these patient and PCP viewpoints.
PCPs saw PRS information as a natural extension of their current practice. The most pressing gap for PRS implementation is evidence for clinical utility. Careful clinical report design can help ensure that benefits are realized and harms are minimized.
The goal of Electronic Medical Records and Genomics (eMERGE) Phase III Network was to return actionable sequence variants to 25,084 consenting participants from 10 different health care institutions ...across the United States. The purpose of this study was to evaluate system-based issues relating to the return of results (RoR) disclosure process for clinical grade research genomic tests to eMERGE3 participants.
RoR processes were developed and approved by each eMERGE institution’s internal review board. Investigators at each eMERGE3 site were surveyed for RoR processes related to the participant’s disclosure of pathogenic or likely pathogenic variants and engagement with genetic counseling. Standard statistical analysis was performed.
Of the 25,084 eMERGE participants, 1444 had a pathogenic or likely pathogenic variant identified on the eMERGEseq panel of 67 genes and 14 single nucleotide variants. Of these, 1077 (74.6%) participants had results disclosed, with 562 (38.9%) participants provided with variant-specific genetic counseling. Site-specific processes that either offered or required genetic counseling in their RoR process had an effect on whether a participant ultimately engaged with genetic counseling (P = .0052).
The real-life experience of the multiarm eMERGE3 RoR study for returning actionable genomic results to consented research participants showed the impact of consent, method of disclosure, and genetic counseling on RoR.
This paper describes one healthcare system's approach to strategically deploying genetic specialists and pharmacists to support the implementation of a precision medicine program. In 2013, Sanford ...Health initiated the development of a healthcare system-wide precision medicine program. Here, we report the necessary staffing including the genetic counselors, genetic counseling assistants, pharmacists, and geneticists. We examined the administrative and electronic medical records data to summarize genetic referrals over time as well as the uptake and results of an enterprise-wide genetic screening test. Between 2013 and 2020, the number of genetic specialists employed at Sanford Health increased by 190%, from 10.1 full-time equivalents (FTEs) to 29.3 FTEs. Over the same period, referrals from multiple provider types to genetic services increased by 423%, from 1438 referrals to 7517 referrals. Between 2018 and 2020, 11,771 patients received a genetic screening, with 4% identified with potential monogenic medically actionable predisposition (MAP) findings and 95% identified with at least one informative pharmacogenetic result. Of the MAP-positive patients, 85% had completed a session with a genetics provider. A strategic workforce staffing and deployment allowed Sanford Health to manage a new genetic screening program, which prompted a large increase in genetic referrals. This approach can be used as a template for other healthcare systems interested in the development of a precision medicine program.
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.
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