Search

Newborn screening (NBS) programs aim to identify affected infants before the onset of treatable disorders. Historically, benefits to the family and society were considered secondary to this clinical benefit; yet, recent discourse defending expanded NBS has argued that screening can in part be justified by secondary benefits, such as learning reproductive risk information to support family planning ('reproductive benefit'). Despite increased attention to these secondary benefits of NBS, stakeholders' values remain unknown. We report a mixed methods study that included an examination of providers' views toward the pursuit of reproductive risk information through NBS, using sickle cell disorder carrier status as an example. We surveyed a stratified random sample of 1615 providers in Ontario, and interviewed 42 providers across 7 disciplines. A majority endorsed the identification of reproductive risks as a goal of NBS (74-77%). Providers' dominant rationale was that knowledge of carrier status is an important and inherent benefit of NBS as it allows people to make reproductive choices, which is consistent with the goals of disease prevention. However, some challenged its appropriateness, questioning its logic, timing and impact on disease prevention. Others were sensitive to intruding on individuals' choices or children's independent rights. While the dominant view is consistent with discourse defending expanded NBS, it deviates from the traditional screening principles that underpin most public health interventions. Broader discussion of the balance between benefits to screened individuals and those to families and societies, in the context of public health programs, is needed. [ABSTRACT FROM AUTHOR]

The expansion of newborn screening (NBS) has been accompanied by debate about what benefits should be achieved and the role of parental discretion in their pursuit. The opportunity to inform parents of reproductive risks is among the most valued additional benefits gained through NBS, and assumes prominence where the primary goal of identifying a treatable condition is not assured. We reviewed 53 unique guidelines addressing prenatal, preconception and newborn screening to examine: (1) how generating reproductive risk information is construed as a benefit of screening; and (2) what conditions support the realization of this benefit. Most preconception and prenatal guidelines – where generating reproductive risk information is described as a primary benefit – required that individuals be given a ‘cascade of choices’, ensuring that each step in the decision-making process was well informed, from deciding to pursue information about reproductive risks to deciding how to manage them. With the exception of three guidelines, NBS policy infrequently attended to the potential for reproductive benefits; further, most guidelines that acknowledged such benefits construed voluntarism narrowly, without attention to the choices attendant on receiving reproductive risk information. This review suggests that prenatal and preconception guidance identifies a coherent framework to support the pursuit of reproductive benefits through population screening programmes. Interestingly, attention to reproductive benefits is increasing among NBS guidance, yet reflection on how such benefits ought to be pursued remains limited. Traditional norms for NBS may require reconsideration where the remit of screening exceeds the primary goal of clinical benefits for infants. [ABSTRACT FROM AUTHOR]

The expansion of newborn screening (NBS) is increasing the generation of incidental results, notably carrier results. Although carrier status is generally understood to be clinically benign, concerns persist that parents may misunderstand its meaning, with deleterious effects on children and their families. Expansion of the NBS panel in Ontario, Canada in 2006 to include sickle cell disorders drew attention to the policy challenge of incidental carrier results. We conducted a study of consumer and provider attitudes to inform policy on disclosure. In this paper, we report the results of (i) qualitative interviews with health-care providers, advocates and parents of carrier infants and (ii) focus groups with new parents and individuals active with the sickle cell community. Lay and provider participants generally believed that carrier results were clinically insignificant. However, some uncertainty persisted among lay consumers in the form of conjecture or doubt. In addition, consumers and advocates who were most informed about the disease articulated insistent yet dissonant claims of clinical significance. Meanwhile, providers referenced research knowledge to offer an equivocal assessment of the possibility and significance of clinically symptomatic carrier status. We conclude that many interpretations of carrier status are in circulation, failing to fit neatly into the categories of ‘clinically significant’ or ‘benign.’ This creates challenges for communicating clearly with parents – challenges exacerbated by inconsistent messages from screening programs regarding the significance of sickle cell carrier status. Disclosure policy related to incidentally generated infant carrier results needs to account for these complex realities. [ABSTRACT FROM AUTHOR]

An apparent consensus governs the management of carrier status information generated incidentally through newborn screening: results cannot be withheld from parents. This normative stance encodes the focus on autonomy and distaste for paternalism that characterize the principles of clinical bioethics. However, newborn screening is a classic public health intervention in which paternalism may trump autonomy and through which parents are — in effect — required to receive carrier information. In truth, the disposition of carrier results generates competing moral infringements: to withhold information or require its possession. Resolving this dilemma demands consideration of a distinctive body of public health ethics to highlight the moral imperatives associated with the exercise of collective authority in the pursuit of public health benefits. (Am J Public Health. 2008;99:210-215. doi: 10.2105/AJPH.2008. 136614) [ABSTRACT FROM AUTHOR]

Purpose: Exome and genome sequencing have rapidly transitioned from research methods to widely used clinical tests for diagnosing rare genetic diseases. We sought to synthesize the topics covered and appraise the development processes of clinical guidance documents generated by genetics professional organizations., Methods: We conducted a scoping review of guidance documents published since 2010, systematically identified in peer-reviewed and gray literature, using established methods and reporting guidelines. We coded verbatim recommendations by topic using content analysis and critically appraised documents using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool., Results: We identified 30 guidance documents produced by 8 organizations (2012-2022), yielding 611 recommendations covering 21 topics. The most common topic related to findings beyond the primary testing indication. Mean AGREE II scores were low across all 6 quality domains; scores for items related to rigor of development were among the lowest. More recently published documents generally received higher scores., Conclusion: Guidance documents included a broad range of recommendations but were of low quality, particularly in their rigor of development. Developers should consider using tools such as AGREE II and basing recommendations on living knowledge syntheses to improve guidance development in this evolving space., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Rare diseases place a significant burden on patients, families, the healthcare system, and society. Evidence on the socioeconomic burden of rare disease is limited and mostly reflects diseases where treatments are available. We developed a framework encompassing recommended cost elements for studies of the socioeconomic burden of rare diseases., Methods: A scoping review, conducted in five databases (Cochrane Library, EconLit, Embase, MEDLINE, and APA PsycINFO), identified English language publications from 2000 to 2021 presenting frameworks developed for determining, measuring or valuing costs for rare or chronic diseases. Cost elements were extracted and used to develop a literature-informed framework. Structured feedback was gathered from experts in rare diseases, health economics/health services, and policy research to revise the framework., Results: Of 2990 records identified, eight papers were included and informed our preliminary framework; three focused on rare disease and five on chronic disease. Following expert input, we developed a framework consisting of nine cost categories (inpatient, outpatient, community, healthcare products/goods, productivity/education, travel/accommodation, government benefits, family impacts, and other), with several cost elements within each category. Our framework includes unique costs, added from the expert feedback, including genetic testing to inform treatment, use of private laboratories or out-of-country testing, family involvement in foundations and organizations, and advocacy costs for special access programs., Conclusions: Our work is the first to identify a comprehensive list of cost elements for rare disease for use by researchers and policy makers to fully capture socioeconomic burden. Use of the framework will increase the quality and comparability of future studies. Future work should focus on measuring and valuing these costs through onset, diagnosis, and post-diagnosis., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Children with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear., Methods: Prescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC., Results: Overall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors., Conclusion: GS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC., Impact: Polypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity., (© 2022. The Author(s).)

Chatbots, web-based artificial intelligence tools that simulate human conversation, are increasingly in use to support many areas of genomic medicine. However, patient preferences towards using chatbots across the range of clinical settings are unknown. We conducted a qualitative study with individuals who underwent genetic testing for themselves or their child. Participants were asked about their preferences for using a chatbot within the genetic testing journey. Thematic analysis employing interpretive description was used. We interviewed 30 participants (67% female, 50% 50 + years). Participants considered chatbots to be inefficient for very simple tasks (e.g., answering FAQs) or very complex tasks (e.g., explaining results). Chatbots were acceptable for moderately complex tasks where participants perceived a favorable return on their investment of time and energy. In addition to achieving this "sweet spot," participants anticipated that their comfort with chatbots would increase if the chatbot was used as a complement to but not a replacement for usual care. Participants wanted a "safety net" (i.e., access to a clinician) for needs not addressed by the chatbot. This study provides timely insights into patients' comfort with and perceived limitations of chatbots for genomic medicine and can inform their implementation in practice., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians. Reanalysis of clinically relevant genes identified diagnoses in 4% (13/287); four were missed by clinical testing. Translational research methods, including analysis of novel candidate genes, identified candidates in 21% (61/287). Of these, 24 families have additional evidence through data sharing to support likely diagnoses (8% of cohort). This study indicates few diagnoses are missed by clinical laboratories, the incremental gain from reanalysis of clinically-relevant genes is modest, and the highest yield comes from validation of novel disease-gene associations. Future implementation of translational research methods, including continued reporting of compelling genes of uncertain significance by clinical laboratories, should be considered to maximize diagnoses., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Extremely preterm infants are prone to hyperbilirubinemia and its sequelae. Currently recommended thresholds for initiating phototherapy in these newborns are consensus-based (CB)., Methods: A multi-site retrospective cohort study of 642 infants born at 24 0/7 to 28 6/7 weeks' gestation, between January 2013 and June 2017, was conducted at three NICUs in Canada. Pre-phototherapy TSB percentile levels at 24 h of age were generated and contrasted with published CB thresholds., Results: Among infants born 24 0/7 to 25 6/7 weeks' gestation, the differences between our TSB percentiles vs. the CB threshold of 85.0 µmol/L were 10.0 µmol/L (95% CI, 6.0-16.0) at the 75th percentile and 35.3 µmol/L (95% CI, 26.1-42.8) at the 95th percentile. Respectively, among infants born at 26 0/7 to 27 6/7 weeks, differences were 19.4 µmol/L (95% CI, 16.8-23.4) and 43.3 µmol/L (95% CI, 34.7-46.9). Born at 28 0/7 to 28 6/7 weeks' gestation, differences between our 75th and 95th TSB percentiles and the CB threshold of 103 µmol/L were 6.9 µmol/L (95% CI, 3.2-12.0) and 36.0 µmol/L (95% CI, 31.0-44.3), respectively., Conclusions: We provide statistically derived pre-phototherapy TSB levels that may clarify patterns of pre-phototherapy TSB levels in extremely preterm infants., Impact: We present statistically derived pre-phototherapy total serum bilirubin levels in a cohort of extremely preterm infants. Most of these preterm infants received phototherapy-some at below currently published thresholds. There are notable differences between our statistically derived pre-phototherapy TSB levels and currently published lower limit TSB thresholds for phototherapy. Our study results assist in the understanding of pre-phototherapy TSB levels in extremely preterm infants., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Little is known about the pattern of genetic testing and frequency of genetic diagnoses among children enrolled in structured complex care programs (CCPs). Such information may inform the suitability of emerging genome diagnostics for this population. The objectives were to describe the proportion of children with undiagnosed genetic conditions despite genetic testing and measure the testing period, types and costs of genetic tests used. A retrospective analysis of 420 children enrolled in Toronto's Hospital for Sick Children's CCP from January 2010 until June 2014 was conducted. Among those who underwent genetic testing ( n = 319; 76%), a random sample of 20% ( n = 63) was further analyzed. A genetic diagnosis was confirmed in 48% of those who underwent testing. Those with no genetic diagnosis underwent significantly more genetic tests than those with a confirmed genetic diagnosis [median interquartile range (IQR): six tests (4-9) vs. three tests (2-4), p = 0.002], more sequence-level tests and a longer, more expensive testing period than those with a genetic diagnosis [median (IQR): length of testing period: 4.12 years (1.73-8.42) vs. 0.35 years (0.12-3.04), p < 0.001; genetic testing costs C$8496 ($4399-$12,480) vs. C$2614 ($1605-$4080), p < 0.001]. A genetic diagnosis was not established for 52% of children. Integrating genome-wide sequencing into clinical care may improve diagnostic efficiency and yield in this population., Competing Interests: The authors declare no conflict of interest. Funding for this project was provided through the Social Paediatrics Research Summer Studentship (SPReSS) program at the Hospital for Sick Children. The funders were not involved in the design or conduct of the study or preparation, review or approval of the manuscript. The authors have indicated they have no financial relationships relevant to this article to disclose.

Objective: To examine the role of primary care providers in informing and supporting families who receive positive screening results., Design: Cross-sectional survey., Setting: Ontario., Participants: Family physicians, pediatricians, and midwives involved in newborn care., Main Outcome Measures: Beliefs, practices, and barriers related to providing information to families who receive positive screening results for their newborns., Results: A total of 819 providers participated (adjusted response rate of 60.9%). Of the respondents, 67.4% to 81.0% agreed that it was their responsibility to provide care to families of newborns who received positive screening results, and 64.2% to 84.8% agreed they should provide brochures or engage in general discussions about the identified conditions. Of the pediatricians, 67.3% endorsed having detailed discussions with families, but only 24.1% of family physicians and 27.6% of midwives endorsed this practice. All provider groups reported less involvement in information provision than they believed they should have. This discrepancy was most evident for family physicians: most stated that they should provide brochures (64.2%) or engage in general discussions (73.5%), but only a minority did so (15.3% and 27.7%, respectively). Family physicians reported insufficient time (42.2%), compensation (52.2%), and training (72.3%) to play this role, and only a minority agreed they were up to date (18.5%) or confident (16.5%) regarding newborn screening., Conclusion: Providers of primary newborn care see an information-provision role for themselves in caring for families who receive positive newborn screening results. Efforts to further define the scope of this role combined with efforts to mitigate existing barriers are warranted.