Search

BackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.MethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).ResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.ConclusionOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

Fragmentation in behavioral and mental health care to children has resulted in suboptimal care and high rates of psychotropic medication use, especially antipsychotic medications (APM). A qualitative study, based on the Theory of Planned Behavior (TPB), aimed to better understand prescribing practices, barriers to optimal treatment, and potential interventions to safeguard the use of APM for children in Kentucky. The most common barrier to optimal care was access to mental health specialists. Social norms and pressure from families contribute to increased medication use. We identify promising interventions to safeguard the use of APM through the lens of the TPB.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

BACKGROUND: Genomic biorepositories will be important tools to help unravel the effect of common genetic variants on risk for common pediatric diseases. Our objective was to explore how parents would respond to the inclusion of children in an opt-out model biobank. METHODS: We conducted semi-structured interviews with parents in hospital-based pediatric clinics. Participants responded to a description of a biorepository already collecting samples from adults. Two coders independently analyzed and coded interviews using framework analysis. Opt-out forms were later piloted in a clinic area. Parental opt-out choices were recorded electronically, with opt-out rates reported here. RESULTS: Parents strongly supported medical research in general and expressed a high level of trust that Vanderbilt University would keep their child's medical information private. Parents were more likely to allow their child's sample to be included in the biorepository than to allow their child to participate in a hypothetical study that would not help or harm their child, but might help other children. Only a minority were able to volunteer a concern raised by the description of the biobank. The opt-out rate was initially high compared with the opt-out rate in the adult biorepository, but after the first week decreased to near the baseline in adult clinics. CONCLUSION: Parents in our study generally support an opt-out model biobank in children. Most would allow their own child's sample to be included. Institutions seeking to build pediatric biobanks may consider the human non-subjects model as a viable alternative to traditional human-subjects biobanks.

In this article, two different scientific approaches to personalized medicine are compared. Biorepository at Vanderbilt University (BioVU) is a genomic biorepository at Vanderbilt University Medical Center in Nashville, TN, USA. Genetic biosamples are collected from leftover clinical blood samples; medical information is derived from an electronic medical records. Greifswald Approach to Individualized Medicine is a research resource at the University of Greifswald, Germany, comprised of clinical records combined with biosamples collected for research. We demonstrate that although both approaches are based on the collection of clinical data and biosamples, different legal milieus present in the USA and Germany as well as slight differences in scientific goals have led to different ‘ethical designs’. While BioVU can successfully operate with an ‘opt-out’ mechanism, an informed consent-based ‘opt-in’ model is indispensable to allow GANI_MED to reach its scientific goals.

Provider claims to conscientious objection have generated a great deal of heated debate in recent years. However, the conflicts that arise when providers make claims to the "conscience" are only a subset of the more fundamental challenges that arise in health care practice when patients and providers come into conflict. In this piece, the author provides an account of patient-provider conflict from within the moral tradition of St. Thomas Aquinas. He argues that the practice of health care providers should be understood as a form of practical reasoning and that this practical reasoning must necessarily incorporate both "moral" and "professional" commitments. In order to understand how the practical reasoning of provider should account for the needs and commitments of the patient and vice versa, he explores the account of dependence provided by Alasdair MacIntyre in his book Dependent Rational Animals. MacIntyre argues that St. Thomas' account of practical reasoning should be extended and adapted to account for the embodied vulnerability of all humans. In light of this insight, providers must view patients not only as the subjects of their moral reflection but also as fellow humans upon whom the provider depends for feedback on the effectiveness and relevance of her practical reasoning. The author argues that this account precludes responsive providers from adopting either moral or professional conclusions on the appropriateness of interventions outside the individual circumstances that arise in particular situations. The adoption of this orientation toward patients will neither eradicate provider-patient conflict nor compel providers to perform interventions to which they object. But this account does require that providers attend meaningfully to the suffering of patients and seek feedback on whether their intervention has effectively addressed that suffering.

About 16% of children have developmental-behavioral disabilities but less than one-third of the children are detected by their health care providers, probably because of the use of informal milestones checklists. The goal of this study is to determine the reliability, validity, accuracy, and utility of a new tool, PEDS: Developmental Milestones (PEDS:DM). Data from a nationally representative sample of 1619 children administered developmental diagnostic measures were mined for items that best predicted performance in each developmental domain. A total of 112 met inclusion criteria, that is, sensitivity/specificity ≥ 70%. For each domain/age level (birth to 8 years of age), sensitivity to performance less than or equal to the 16th percentile on diagnostic measures was 83% and specificity was 84%. Reliability was high (test—retest, .98 to .99; interrater, .82 to .96; κ, .81). The readability level was 1.8 grades (range 1.1 to 2.6). The PEDS:DM appears to be a validated, accurate alternative to informal milestones checklists that are a probable contributor to underdetection of children with delays and disabilities.

Genomic sequencing is being rapidly introduced into pediatric clinical practice. The results of sequencing are distinctive for their complexity and subsequent challenges of interpretation for generalist and specialist pediatricians, parents, and patients. Pediatricians therefore need to prepare for the professionally responsible disclosure of sequencing results to parents and patients and guidance of parents and patients in the interpretation and use of these results, including managing uncertain data. This article provides an ethical framework to guide and evaluate the professionally responsible disclosure of the results of genomic sequencing in pediatric practice. The ethical framework comprises 3 core concepts of pediatric ethics: the best interests of the child standard, parental surrogate decision-making, and pediatric assent. When recommending sequencing, pediatricians should explain the nature of the proposed test, its scope and complexity, the categories of results, and the concept of a secondary or incidental finding. Pediatricians should obtain the informed permission of parents and the assent of mature adolescents about the scope of sequencing to be performed and the return of results.

report on a program that involves state-offered carrier screening for cystic fibrosis, spinal mus-cular atrophy, and fragile X for the entire population of Israel, with screening for a wide array of additional diseases selected based on a combination of ethnicity, religious affiliation, and locality of origin. To their credit, Zlotogora et al.

Next generation genomic sequencing technologies (including whole genome or whole exome sequencing) are being increasingly applied to clinical care. Yet, the breadth and complexity of sequencing information raise questions about how best to communicate and return sequencing information to patients and families in ways that facilitate comprehension and optimal health decisions. Obtaining answers to such questions will require multidisciplinary research. In this paper, we focus on how psychological science research can address questions related to clinical genomic sequencing by explaining emotional, cognitive, and behavioral processes in response to different types of genomic sequencing information (e.g., diagnostic results and incidental findings). We highlight examples of psychological science that can be applied to genetic counseling research to inform the following questions: (1) What factors influence patients' and providers' informational needs for developing an accurate understanding of what genomic sequencing results do and do not mean?; (2) How and by whom should genomic sequencing results be communicated to patients and their family members?; and (3) How do patients and their families respond to uncertainties related to genomic information?

The inclusion of genomic data in the electronic health record raises important ethical, legal, and social issues. In this article, we highlight these challenges and discuss potential solutions. We provide a brief background on the current state of electronic health records in the context of genomic medicine, discuss the importance of equitable access to genome-enabled electronic health records, and consider the potential use of electronic health records for improving genomic literacy in patients and providers. We highlight the importance of privacy, access, and security, and of determining which genomic information is included in the electronic health record. Finally, we discuss the challenges of reporting incidental findings, storing and reinterpreting genomic data, and nondocumentation and duty to warn family members at potential genetic risk.

Biorepositories collecting human specimens and health information have proliferated in recent years. Efforts to set a range of policies related to biorepositories, including those related to procedures for obtaining informed consent and recontacting participants, have been hindered by a paucity of data on the diverse forms biorepositories take and the variety of institutional settings where they are established. A recent survey demonstrates in detail, for the first time, the diversity of biorepositories in the USA. See research article: http://genomemedicine.com/content/5/1/3

Incidental findings have long posed challenges for healthcare providers, but the scope and scale of these challenges have increased with the introduction of new technologies. This article assesses the impact of incidental findings on the introduction of prospective pharmacogenomic testing into clinical use. Focusing on the challenges of the incidentalome, the large set of incidental findings potentially generated through genotyping, the paper argues that provisional approaches to managing incidental findings may be implemented if necessary to allow benefits of pharmacogenomic testing to be realized in the clinical setting. In the longer term, approaches to returning incidental findings may need to focus on limiting the number of incidental findings to a number that can be addressed by patients and providers.

This paper examines the historical rise of both cardiopulmonary resuscitation (CPR) and the do-not-resuscitate (DNR) order and the wisdom of their continuing status in U.S. hospital practice and policy. The practice of universal presumed consent to CPR and the resulting DNR policy are the products of a particular time and were responses to particular problems. In order to keep the excesses of technology in check, the DNR policies emerged as a response to the in-hospital universal presumed consent to CPR. We live with this historical concretion, which seems to perpetuate a false culture that the patient's wishes must be followed. The authors are critical of the current U.S. climate, where CPR and DNR are viewed as two among a panoply of patient choices, and point to UK practice as an alternative. They conclude that physicians in the United States should radically rethink approaches to CPR and DNR.

In the Policy Forum “Children and population biobanks” (14 August, p. [818][1]), D. Gurwitz et al. proposed that DNA information from children should not be shared from population databanks until those children reach adulthood and give specific consent. This proposal is flawed. First, the authors place too much weight on consent. The potential harm posed by data sharing can be mitigated by limiting the data to be shared, removing identifiable elements, and maintaining thorough oversight. BioVU, Vanderbilt's resource of residual blood samples and information from electronic medical records, uses de-identification during data and sample collection and again before sharing data, as well as careful internal and external oversight. Moreover, limited-access research databases are likely to be relatively unattractive sources of personal and genetic information for hackers. Any concerns about the coverage of the Genetic Information Nondiscrimination Act should be addressed through legislation. Second, the authors suggest that parental permission is an appropriate justification for permitting information from disease-specific databanks to be shared. This justification fails because it falls into the trap of the therapeutic misconception. Therapeutic research involves trying a new intervention, such as a new drug. Sharing DNA information with other investigators is not therapeutic because it is very unlikely to help any particular child in the short term. Their proffered distinction would also undermine the moral acceptability of the National Children's Study, given that the data sharing planned in this population-based study would be deemed unacceptable. Third, waiting 18 to 21 years to combine data from various sites, an essential step in examining how genetic variation affects the health of children, means that research on children will always lag a generation behind and will reflect only the medicine and environment of years gone by. [1]: /lookup/doi/10.1126/science.1173284

There is a growing consensus that results generated through multiplex genetic tests, even those produced as a part of research, should be reported to providers and patients when they are considered “actionable,” that is, when they could be used to inform some potentially beneficial clinical action. However, there remains controversy over the precise criterion that should be used in identifying when a result meets this standard. In this paper, we seek to refine the concept of “actionability” by exploring one proposed use for genetic test results. We argue that genetic test results indicating that a patient is at risk for developing a chronic health condition should not be considered actionable if the only potential value of that result is to motivate patients to make changes in their health behaviors. Since the empirical research currently available on this question is equivocal, we explore relevant psychological theories of human motivation to demonstrate that current theory does not support the assumption that information about genetic risk will be motivating to most patients in their attempts to make changes in health behaviors.