Robin Z. Hayeems

Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%; P value=1.42E−05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%; P value=0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

What is a Meaningful Result? Disclosing the Results of Genomic Research in Autism to Research Participants

Developments in genomics research have been accompanied by a controversial ethical injunction: that researchers disclose individually relevant research results to research participants. With the explosion of genomic research on complex psychiatric conditions such as autism, researchers must increasingly contend with whether – and which results – to report. We conducted a qualitative study with researchers and participants involved in autism genomics research, including 4 focus groups and 23 interviews with parents of autistic children, and 23 interviews with researchers. Respondents considered genomic research results ‘reportable’ when results were perceived to explain cause, and answer the question ‘why;’ that is, respondents set a standard for reporting individually relevant genetic research results to individual participants that is specific to autism, reflecting the metaphysical value that genetic information is seen to offer in this context. In addition to this standard of meaning, respondents required that results be deemed ‘true.’ Here, respondents referenced standards of validity that were context nonspecific. Yet in practice, what qualified as ‘true’ depended on evidentiary standards within specific research disciplines as well as fundamental, and contested, theories about how autism is ‘genetic.’ For research ethics, these finding suggest that uniform and context-free obligations regarding result disclosure cannot readily be specified. For researchers, they suggest that result disclosure to individuals should be justified not only by perceived meaning but also by clarity regarding appropriate evidentiary standards, and attention to the status of epistemological debates regarding the nature and cause of disorders.

Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care

Developments in genomics, including next-generation sequencing technologies, are expected to enable a more personalized approach to clinical care, with improved risk stratification and treatment selection. In oncology, personalized medicine is particularly advanced and increasingly used to identify oncogenic variants in tumor tissue that predict responsiveness to specific drugs. Yet, the translational research needed to validate these technologies will be conducted in patients with late-stage cancer and is expected to produce results of variable clinical significance and incidentally identify genetic risks. To explore the experiential context in which much of personalized cancer care will be developed and evaluated, we conducted a qualitative interview study alongside a pilot feasibility study of targeted DNA sequencing of metastatic tumor biopsies in adult patients with advanced solid malignancies. We recruited 29/73 patients and 14/17 physicians; transcripts from semi-structured interviews were analyzed for thematic patterns using an interpretive descriptive approach. Patient hopes of benefit from research participation were enhanced by the promise of novel and targeted treatment but challenged by non-findings or by limited access to relevant trials. Family obligations informed a willingness to receive genetic information, which was perceived as burdensome given disease stage or as inconsequential given faced challenges. Physicians were optimistic about long-term potential but conservative about immediate benefits and mindful of elevated patient expectations; consent and counseling processes were expected to mitigate challenges from incidental findings. These findings suggest the need for information and decision tools to support physicians in communicating realistic prospects of benefit, and for cautious approaches to the generation of incidental genetic information.

How patients experience progressive loss of visual function: a model of adjustment using qualitative methods

Background: People with retinitis pigmentosa (RP) experience functional and psychological challenges as they adjust to progressive loss of visual function. The authors aimed to understand better the process of adjusting to RP in light of the emotional suffering associated with this process. Methods: Adults with RP were recruited from the Foundation Fighting Blindness and the Wilmer Eye Institute in Baltimore. Focus groups and semistructured interviews addressed the process of adjusting to RP and were audiotaped and transcribed. The transcripts were analysed qualitatively in order to generate a model of adjustment. Results: A total of 43 individuals participated. It was found that, on diagnosis, people with RP seek to understand its meaning in their lives. Mastering the progressive functional implications associated with RP is contingent upon shifting personal identity from a sighted to a visually impaired person. In this sample, six participants self identified as sighted, 10 self identified as in transition, and 27 self identified as visually impaired. This adjustment process can be understood in terms of a five stage model of behaviour change. Conclusions: The proposed model presents one way to understand the process of adjusting to RP and could assist ophthalmologists in meeting their moral obligation to lessen patients’ suffering, which arises in the course of their adjustment to progressive loss of visual function.

Citizens’ Values Regarding Research With Stored Samples From Newborn Screening in Canada

OBJECTIVES: Newborn screening (NBS) programs may store bloodspot samples and use them for secondary purposes. Recent public controversies and lawsuits over storage and secondary uses underscore the need to engage the public on these issues. We explored Canadian values regarding storage and use of NBS samples for various purposes and the forms of parental choice for anonymous research with NBS samples. METHODS: We conducted a mixed-methods, public engagement study comprising 8 focus groups (n = 60), an educational component, deliberative discussion, and pre- and post-questionnaires assessing knowledge and values toward storage and parental choice. RESULTS: Canadian citizens supported the storage of NBS samples for quality control, confirmatory diagnosis, and future anonymous research (>90%). There was broad support for use of NBS samples for anonymous research; however, opinions were split about the extent of parental decision-making. Support for a “routinized” approach rested on trust in authorities, lack of concern for harms, and an assertion that the population’s interest took priority over the interests of individuals. Discomfort stemmed from distrust in authorities, concern for harms, and prioritizing individual interests, which supported more substantive parental choice. Consensus emerged regarding the need for greater transparency about the storage and secondary use of samples. CONCLUSIONS: Our study provides novel insights into the values that underpin citizens’ acceptance and discomfort with routine storage of NBS samples for research, and supports the need to develop well-designed methods of public education and civic discourse on the risks and benefits of the retention and secondary use of NBS samples.

A Systematic Review of the Effects of Disclosing Carrier Results Generated Through Newborn Screening

Evidence on the effects of disclosing carrier results identified through newborn screening (NBS) is needed to develop effective strategies for managing these results, and to inform debate about contradictory policies governing genetic testing in minors in the context of NBS relative to clinical care. This is likely to be even more important as technological opportunities for carrier identification through NBS increase. We report the results of a systematic review of evidence related to the generation of carrier results through NBS to summarize what is known about: (1) the outcomes associated with these results; (2) the best strategies for providing information and follow-up care to parents; and (3) the impact they have on reproductive decision-making. Our study expands the existing body of knowledge and identifies gaps in the evidence base. As key players in the management of carrier results clinically, genetic counselors are well positioned to engage in formative research and policy development in this area.

Reconsidering reproductive benefit through newborn screening: a systematic review of guidelines on preconception, prenatal and newborn screening.

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.

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Health system strategies supporting transition to adult care

Background The transition from paediatric to adult care is associated with poor clinical outcomes, increased costs and low patient and family satisfaction. However, little is known about health system strategies to streamline and safeguard care for youth transitioning to adult services. Moreover, the needs of children and youth are often excluded from broader health system reform discussions, leaving this population especially vulnerable to system ‘disintegration’. Objectives (1) To explore the international policy profile of paediatric-to-adult care transitions, and (2) to document policy objectives, initiatives and outcomes for jurisdictions publicly committed to addressing transition issues. Methods An international policy scoping review of all publicly available government documents detailing transition-related strategies was completed using a web-based search. Our analysis included a comparable cohort of nine wealthy Organisation for Economic Co-operation and Development (OECD) jurisdictions with Beveridge-style healthcare systems (deemed those most likely to benefit from system-level transition strategies). Results Few jurisdictions address transition of care issues in either health or broader social policy documents. While many jurisdictions refer to standardised practice guidelines, a few report the intention to use powerful policy levers (including physician remuneration and non-physician investments) to facilitate the uptake of best practice. Most jurisdictions do not address the policy infrastructure required to support successful transitions, and rigorous evaluations of transition strategies are rare. Conclusions Despite the well-documented risks and costs associated with a poor transition from paediatric to adult care, little policy attention has been paid to this issue. We recommend that healthcare providers engage health system planners in the design and evaluation of system-level, policy-sensitive transition strategies.

Questioning the Consensus: Managing Carrier Status Results Generated by Newborn Screening

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.