Public health newborn screening (NBS) programs provide population-scale ascertainment of rare, treatable conditions that require urgent intervention. Tandem mass spectrometry (MS/MS) is currently ...used to screen newborns for a panel of rare inborn errors of metabolism (IEMs)
. The NBSeq project evaluated whole-exome sequencing (WES) as an innovative methodology for NBS. We obtained archived residual dried blood spots and data for nearly all IEM cases from the 4.5 million infants born in California between mid-2005 and 2013 and from some infants who screened positive by MS/MS, but were unaffected upon follow-up testing. WES had an overall sensitivity of 88% and specificity of 98.4%, compared to 99.0% and 99.8%, respectively for MS/MS, although effectiveness varied among individual IEMs. Thus, WES alone was insufficiently sensitive or specific to be a primary screen for most NBS IEMs. However, as a secondary test for infants with abnormal MS/MS screens, WES could reduce false-positive results, facilitate timely case resolution and in some instances even suggest more appropriate or specific diagnosis than that initially obtained. This study represents the largest, to date, sequencing effort of an entire population of IEM-affected cases, allowing unbiased assessment of current capabilities of WES as a tool for population screening.
Many scientists and doctors hope that affordable genome sequencing will lead to more personalized medical care and improve public health in ways that will benefit children, families, and society more ...broadly. One hope in particular is that all newborns could be sequenced at birth, thereby setting the stage for a lifetime of medical care and self‐directed preventive actions tailored to each child's genome. Indeed, commentators often suggest that universal genome sequencing is inevitable. Such optimism can come with the presumption that discussing the potential limits, cost, and downsides of widespread application of genomic technologies is pointless, excessively pessimistic, or overly cautious. We disagree. Given the pragmatic challenges associated with determining what sequencing data mean for the health of individuals, the economic costs associated with interpreting and acting on such data, and the psychosocial costs of predicting one's own or one's child's future life plans based on uncertain testing results, we think this hope and optimism deserve to be tempered.
In the analysis that follows, we distinguish between two reasons for using sequencing: to diagnose individual infants who have been identified as sick and to screen populations of infants who appear to be healthy. We also distinguish among three contexts in which sequencing for either diagnosis or screening could be deployed: in clinical medicine, in public health programs, and as a direct‐to‐consumer service. Each of these contexts comes with different professional norms, policy considerations, and public expectations. Finally, we distinguish between two main types of genome sequencing: targeted sequencing, where only specific genes are sequenced or analyzed, and whole‐exome or whole‐genome sequencing, where all the DNA or all the coding segments of all genes are sequenced and analyzed.
In a symptomatic newborn, targeted or genome‐wide sequencing can help guide other tests for diagnosis or for specific treatment that is urgently needed. Clinicians use the infant's symptoms (or phenotype) to interrogate the sequencing data. These same complexities and uncertainties, however, limit the usefulness of genome‐wide sequencing as a population screening tool. While we recognize considerable benefit in using targeted sequencing to screen for or detect specific conditions that meet the criteria for inclusion in newborn screening panels, use of genome‐wide sequencing as a sole screening tool for newborns is at best premature. We conclude that sequencing technology can be beneficially used in newborns when that use is nuanced and attentive to context.
Integrating data across heterogeneous research environments is a key challenge in multi-site, collaborative research projects. While it is important to allow for natural variation in data collection ...protocols across research sites, it is also important to achieve interoperability between datasets in order to reap the full benefits of collaborative work. However, there are few standards to guide the data coordination process from project conception to completion. In this paper, we describe the experiences of the Clinical Sequence Evidence-Generating Research (CSER) consortium Data Coordinating Center (DCC), which coordinated harmonized survey and genomic sequencing data from seven clinical research sites from 2020 to 2022. Using input from multiple consortium working groups and from CSER leadership, we first identify 14 lessons learned from CSER in the categories of communication, harmonization, informatics, compliance, and analytics. We then distill these lessons learned into 11 recommendations for future research consortia in the areas of planning, communication, informatics, and analytics. We recommend that planning and budgeting for data coordination activities occur as early as possible during consortium conceptualization and development to minimize downstream complications. We also find that clear, reciprocal, and continuous communication between consortium stakeholders and the DCC is equally important to maintaining a secure and centralized informatics ecosystem for pooling data. Finally, we discuss the importance of actively interrogating current approaches to data governance, particularly for research studies that straddle the research-clinical divide.
Research data coordination is a challenging process with few guiding standards. This study identifies 14 lessons learned from data coordination in the Clinical Sequence Evidence-Generating Research (CSER) Consortium and offers 11 recommendations for data coordination in other multi-institutional research projects in the areas of planning, communication, informatics, and analytics.
abstract Throughout the COVID-19 pandemic, the US has struggled with many aspects of the public health response, from determining where transmission is occurring to building trust with communities ...and implementing interventions. Three factors have contributed to these challenges: insufficient local public health capacity, siloed interventions, and underuse of a cluster-based approach to outbreak response. In this article we introduce Community-based Outbreak Investigation and Response (COIR), a local public health strategy developed during the COVID-19 pandemic that addresses these shortcomings. COIR can help local public health entities conduct disease surveillance more effectively, take a more proactive and efficient approach to mitigating transmission, coordinate response efforts, build community trust, and advance equity. We offer a practitioner's lens, informed through on-the-ground experience and engagement with policy makers, to highlight the financing, workforce, data system, and information-sharing policy changes needed to scale up COIR throughout the country. COIR can enable the US public health system to develop effective solutions to many of today's public health challenges and improve the nation's preparedness for public health crises in the years to come.
Throughout the COVID-19 pandemic, the US has struggled with many aspects of the public health response, from determining where transmission is occurring to building trust with communities and ...implementing interventions. Three factors have contributed to these challenges: insufficient local public health capacity, siloed interventions, and underuse of a cluster-based approach to outbreak response. In this article we introduce Community-based Outbreak Investigation and Response (COIR), a local public health strategy developed during the COVID-19 pandemic that addresses these shortcomings. COIR can help local public health entities conduct disease surveillance more effectively, take a more proactive and efficient approach to mitigating transmission, coordinate response efforts, build community trust, and advance equity. We offer a practitioner's lens, informed through on-the-ground experience and engagement with policy makers, to highlight the financing, workforce, data system, and information-sharing policy changes needed to scale up COIR throughout the country. COIR can enable the US public health system to develop effective solutions to many of today's public health challenges and improve the nation's preparedness for public health crises in the years to come.
The potential application of whole-genome sequencing (WGS) to state-mandated standard newborn screening (NBS) challenges the traditional public health approach to NBS and raises ethical, policy, and ...clinical practice issues. This article examines the perspectives and values of diverse healthy pregnant women and parents of children diagnosed with a primary immunodeficiency disorder about traditional NBS and expanded NBS with the use of WGS.
We conducted 4 focus groups (3 in English and 1 in Spanish) with socioeconomically and ethnically diverse pregnant women (n = 26), and a comparison group with parents of children diagnosed with a primary immunodeficiency disorder (n = 5).
Pediatric policy-relevant themes that emerged from our analysis of the focus group data are presented within 4 categories: (1) perspectives on traditional NBS, (2) informed consent, (3) return of results, and (4) storage and retrieval of results. Analyses indicate that study participants desired greater inclusion in the NBS process. Despite an optimistic orientation to the potential benefits and limited harms likely to result from genomic applications of NBS, parents voiced concerns about privacy and control over test results. Limited trust in the medical system and the state-run NBS program informed these concerns.
Expanded NBS with WGS for pediatricians may require management of more genetic conditions, including mutations that convey risk to both the child and parents for adult-onset disorders, and an informed-consent process to manage the genomic data and storage of blood spots. Attention to how these technologies are understood in diverse populations is needed for effective implementation.
Newborn screening (NBS) for rare conditions is performed in all 50 states in the USA. We have partnered with the California Department of Public Health Genetic Disease Laboratory to determine whether ...sufficient DNA can be extracted from archived dried blood spots (DBS) for next‐generation sequencing in the hopes that next‐generation sequencing can play a role in NBS. We optimized the DNA extraction and sequencing library preparation protocols for residual infant DBS archived over 20 years ago and successfully obtained acceptable whole exome and whole genome sequencing data. This sequencing study using DBS DNA without whole genome amplification prior to sequencing library preparation provides evidence that properly stored residual newborn DBS are a satisfactory source of DNA for genetic studies.
Newborn screening (NBS) for rare conditions is performed in all 50 states in the USA. We optimized the DNA extraction and sequencing library preparation protocols for residual infant dried blood spots (DBS) archived over 20 years ago and successfully obtained acceptable whole exome and whole genome sequencing data. This pilot study using DBS DNA without whole genome amplification prior to sequencing library preparation shows that properly stored residual newborn DBS are a satisfactory source of DNA for genetic studies.
Objective
We aimed to determine the frequency of accepting secondary findings in families undergoing exome sequencing in prenatal and pediatric settings.
Methods
This was a secondary analysis of ...prospectively enrolled patients undergoing trio exome sequencing for congenital anomalies or developmental disorders in prenatal and pediatric settings, in which families were offered receiving secondary findings (initially assessed in the proband and, if identified, then in the parents). The primary outcome was frequency of accepting secondary findings. Secondary outcomes included frequency of acceptance in prenatal versus pediatric settings, and sociodemographic differences between those who accepted versus declined secondary findings.
Results
There were 682 families included in the cohort (289 prenatal and 393 pediatric). Overall, 84% (576/682) of families accepted secondary findings: 86.2% (249/289) of families undergoing prenatal versus 83.2% (327/393) pediatric (p = 0.30) testing. Secondary findings were identified in 2.6% (15/576) of cases, with no difference between prenatal and pediatric settings. There were no differences in sociodemographics between families that accepted versus declined secondary findings.
Conclusion
The majority of families undergoing exome sequencing accepted secondary findings; this did not differ in prenatal versus pediatric settings. This highlights the need for guidance surrounding the offer of secondary findings in the prenatal setting.
Key Points
What's already known about this topic?
Clinically actionable secondary findings may be identified when clinical exome sequencing is performed.
Reporting of secondary findings in the prenatal and pediatric settings is ethically challenging; the American College of Medical Genetics & Genomics recommends that this information be offered in the pediatric setting.
There is no professional guidance and limited information about patient preferences surrounding secondary findings when exome sequencing is performed in the prenatal setting.
What does this study add?
A majority of families undergoing exome sequencing in both the pediatric and prenatal settings request the reporting of secondary findings.
Frequency of requesting secondary findings was similar among families undergoing prenatal and pediatric exome sequencing.
Frequency of requesting secondary findings was similar among families undergoing prenatal exome sequencing with ongoing pregnancies and after pregnancy termination or loss.
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