Newborn screening for neurodevelopmental diseases: Are we there yet?

In the US, newborn screening (NBS) is a unique health program that supports health equity and screens virtually every baby after birth, and has brought timely treatments to babies since the 1960's. With the decreasing cost of sequencing and the improving methods to interpret genetic data, there is an opportunity to add DNA sequencing as a screening method to facilitate the identification of babies with treatable conditions that cannot be identified in any other scalable way, including highly penetrant genetic neurodevelopmental disorders (NDD). However, the lack of effective dietary or drug-based treatments has made it nearly impossible to consider NDDs in the current NBS framework, yet it is anticipated that any treatment will be maximally effective if started early. Hence there is a critical need for large scale pilot studies to assess if and how NDDs can be effectively screened at birth, if parents desire that information, and what impact early diagnosis may have. Here we attempt to provide an overview of the recent advances in NDD treatments, explore the possible framework of setting up a pilot study to genetically screen for NDDs, highlight key technical, practical, and ethical considerations and challenges, and examine the policy and health system implications.

Aiming High: Monitoring Population Level Indicators of Child Wellbeing as a Goal of Community-Academic Partnerships.

INTRODUCTION: Community-academic partnerships (CAPs) aim to improve neighborhood population health. Though measuring the impact of partnership activities at a population level can be difficult, evaluating indicators of wellbeing may increase understanding of how communities benefit from CAPs. This study examined child health indicators over time in two low-income, predominantly Black/African American and Hispanic communities where partnerships between an academic child development center and community coalitions were formed with the intention of improving child well-being. METHODS: Trends in three child wellbeing indicators (graduation rates, kindergarten readiness, and proportion of youth in school and/or employed) were compared between two CAP communities and several neighboring comparison communities. Data between 2011 and 2017 were analyzed to calculate percent change from baseline and mapped using ArcGIS to visualize trends by zip code. Proportions of youth meeting benchmarks were also determined. RESULTS: Kindergarten readiness and high-school graduation rates improved in CAP communities but not in geographically proximal and socioeconomically similar comparison communities. No improvements were found in the proportion of youth in school or employed. DISCUSSION: This study revealed population-level indicators improved over time in CAP communities. Because community-level child health and wellbeing are influenced by many factors, this correlation is not proof of a causal relationship. Assessing population level indicators can nonetheless provide insight into the benefit of CAPs, and the commitment to monitoring such outcomes can itself advance how academic and community partners plan activities and set long-term goals.

Foundation of the Newborn Screening Translational Research Network and its tools for research.

In the past 20 years, several policy activities were undertaken that shaped today's newborn screening (NBS) programs and their associated NBS research activities: the Newborn Screening Task Force Report; the Child Health Act of 2000, Screening for Heritable Disorders; the American College of Medical Genetics and Genomics' (ACMG's) Newborn Screening Uniform Panel; and the ACMG expert panel to examine the development of a national collaborative study system for rare genetic diseases. These activities helped conceptualize the Newborn Screening Translational Research Network (NBSTRN) infrastructure and lay the foundation for its current activities. After 10 years, NBSTRN has grown into an organization that provides tools and resources for researchers to conduct research relevant to NBS programs for rare diseases for which data has been siloed locally. Infrastructure includes tools for the analytical and clinical validation of screening tests; the collection, analysis, sharing, and reporting of longitudinal laboratory and clinical data on newborn-screened individuals; and a web-based tool that allows researchers to acquire dried blood spots available for use in research from state NBS programs. NBSTRN also provides tools for researchers such as informed consent templates, disease registries, state NBS profiles, and consultation on planning pilot studies. In time, the growing data will become a resource itself.

Including ELSI research questions in newborn screening pilot studies.

BACKGROUND: The evidence review processes for adding new conditions to state newborn screening (NBS) panels rely on data from pilot studies aimed at assessing the potential benefits and harms of screening. However, the consideration of ethical, legal, and social implications (ELSI) of screening within this research has been limited. This paper outlines important ELSI issues related to newborn screening policy and practices as a resource to help researchers integrate ELSI into NBS pilot studies. APPROACH: Members of the Bioethics and Legal Workgroup for the Newborn Screening Translational Research Network facilitated a series of professional and public discussions aimed at engaging NBS stakeholders to identify important existing and emerging ELSI challenges accompanying NBS. RESULTS: Through these engagement activities, we identified a set of key ELSI questions related to (1) the types of results parents may receive through newborn screening and (2) the initiation and implementation of NBS for a condition within the NBS system. CONCLUSION: Integrating ELSI questions into pilot studies will help NBS programs to better understand the potential impact of screening for a new condition on newborns and families, and make crucial policy decisions aimed at maximized benefits and mitigating the potential negative medical or social implications of screening.

The Interprofessional/Family-Centered-Care Observation Rubric (I-FOR): Results of a Multicenter Study of a New Measure of Educational Outcomes.

Introduction The ability to provide family-centered care (FCC) and the ability to work in interprofessional care teams (IPC) are essential educational outcomes in graduate training programs. Lack of standardized measures leave programs to rely on idiosyncratic methods to monitor outcomes. We developed a faculty observation tool as part of an effort to create a national quality improvement database. We present evidence for the feasibility and validity of the faculty observation tool. Methods Trainees and faculty at four independent training programs participated. Nineteen maternal and child health disciplines were represented. Faculty supervisors rated trainees using the new measure (I-FOR), and trainees completed related subscales of a previously developed self-report measure, the core competency measure (CCM). Faculty provided qualitative feedback regarding the I-FOR in a separate questionnaire. Results Faculty (n = 78) completed the I-FOR on 86 trainees (86/92 = 93%) and reported satisfaction with completing the measures. The I-FOR demonstrated good internal consistency (Cronbach's alpha > 0.930) and test-retest reliability (IPC r = 0.862, FCC r = 0.823, p < 0.001). Greater than 95% of participants reported that the I-FOR accurately addressed the relevant skills for each practice domain. The I-FOR showed no correlation with the CCM. Significant improvements over time in the I-FOR ratings were demonstrated in three out of four programs. Discussion The I-FOR demonstrated good internal consistency and test-retest reliability. Faculty responses provide evidence for the feasibility and validity of the instrument. Self-report and faculty-observation measures both increased with training but were not correlated with each other.

Child Rights and Clinical Bioethics: Historical Reflections on Modern Medicine and Ethics.

Why might pediatric bioethicists in the United States reject the U.N. Convention on the Rights of the Child (CRC) as a framework for resolving ethical issues? The essays in this issue present arguments and counterarguments regarding the usefulness of the CRC in various clinical and research cases. But underlying this debate are two historical factors that help explain the seeming paradox of pediatric bioethicists' arguing against child's rights. First, the profession of clinical bioethics emerged in the 1970s as one component of modern medicine's focus on improving health through the application of technologically sophisticated treatments. The everyday work of U.S. bioethicists thus usually involves emerging technologies or practices in clinical or laboratory settings; the articles of the CRC, in contrast, seem better suited to addressing broad policy issues that affect the social determinants of health. Second, U.S. child health policy veered away from a more communitarian approach in the early 20th century for reasons of demography that were reinforced by ideology and concerns about immigration. The divide between clinical medicine and public health in the United States, as well as the relatively meager social safety net, are not based on a failure to recognize the rights of children. Indeed, there is some historical evidence to suggest that "rights language" has hindered progress on child health and well-being in the United States. In today's political climate, efforts to ensure that governments pledge to treat children in accordance with their status as human beings (a child right's perspective) are less likely to improve child health than robust advocacy on behalf of children's unique needs, especially as novel models of health-care financing emerge.

Phenylketonuria Scientific Review Conference: state of the science and future research needs.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 µmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 µmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

An Expanded Approach to the Ascertainment of Children and Youth With Special Health Care Needs.

OBJECTIVE: To describe the prevalence, characteristics, and health-related outcomes of children with diagnosed health conditions and functional difficulties who do not meet criteria for having a special health care need based on the traditional scoring of the Children with Special Health Care Needs (CSHCN) Screener. METHODS: Data come from the 2016 to 2021 National Survey of Children's Health (n = 225 443). Child characteristics and health-related outcomes were compared among 4 mutually exclusive groups defined by CSHCN Screener criteria and the presence of both conditions and difficulties. RESULTS: Among children who do not qualify as children and youth with special health care needs (CYSHCN) on the CSHCN Screener, 6.8% had ≥1 condition and ≥1 difficulty. These children were more likely than CYSHCN to be younger, female, Hispanic, uninsured, privately insured, living in a household with low educational attainment, have families with more children and a primary household language other than English. After adjustment, non-CYSHCN with ≥1 conditions and ≥1 difficulty were less likely than CYSHCN, but significantly more likely than other non-CYSHCN, to have ≥2 emergency department visits, have unmet health care needs, not meet flourishing criteria, live in families that experienced child health-related employment impacts and frustration accessing services. Including these children in the calculation of CYSHCN prevalence increases the national estimate from 19.1% to 24.6%. CONCLUSIONS: Approximately 4 million children have both a diagnosed health condition and functional difficulties but are not identified as CYSHCN. An expanded approach to identify CYSHCN may better align program and policy with population needs.

Shared Decision-Making at the Intersection of Disability, Culture, and Language Accessibility: An Educational Session for Medical Students.

Introduction: People with disabilities and those with non-English language preferences have worse health outcomes than their counterparts due to barriers to communication and poor continuity of care. As members of both groups, people who are Deaf users of American Sign Language have compounded health disparities. Provider discomfort with these specific demographics is a contributing factor, often stemming from insufficient training in medical programs. To help address these health disparities, we created a session on disability, language, and communication for undergraduate medical students. Methods: This 2-hour session was developed as a part of a 2020 curriculum shift for a total of 404 second-year medical student participants. We utilized a retrospective postsession survey to analyze learning objective achievement through a comparison of medians using the Wilcoxon signed rank test (α = .05) for the first 2 years of course implementation. Results: When assessing 158 students' self-perceived abilities to perform each of the learning objectives, students reported significantly higher confidence after the session compared to their retrospective presession confidence for all four learning objectives (ps < .001, respectively). Responses signifying learning objective achievement (scores of 4, probably yes, or 5, definitely yes), when averaged across the first 2 years of implementation, increased from 73% before the session to 98% after the session. Discussion: Our evaluation suggests medical students could benefit from increased educational initiatives on disability culture and health disparities caused by barriers to communication, to strengthen cultural humility, the delivery of health care, and, ultimately, health equity.

Quality of Life and Well-Being for Children and Youth With Special Health Care Needs and their Families: A Vision for the Future.

OBJECTIVES: To fulfill the promise of a life of dignity, autonomy, and independence for children and youth with special health care needs (CYSHCN) and their families, greater value must be assigned to meaningful outcomes, such as quality of life and well-being. METHODS: Despite decades of research, programs, and measurements addressing quality of life and well-being for CYSHCN and their families, there still is no consensus on how to measure, implement, or achieve them. RESULTS: As the US health care system strives to reach the health care goals of safe, efficient, effective, equitable, timely, and patient-centered care, youth and families must be equal partners at all levels of the health care system-from clinical decision making to designing and implementing programs and policies. CONCLUSIONS: The health care system must systematically measure the priorities of CYSHCN and their families. It also must incorporate data on quality of life and well-being when developing services, supports, and systems that help CYSHCN and their families to flourish rather than hindering them.

A Quality Improvement Network for Interdisciplinary Training in Developmental Disabilities.

Children with developmental disabilities (DD), such as autism spectrum disorder (ASD), have complex health and developmental needs that require multiple service systems and interactions with various professionals across disciplines. The growing number of children and youth identified with ASD or DD, including anxiety and depression, has increased demand for services and need for highly qualified pediatric providers. Federally funded Leadership Education in Neurodevelopmental and related Disabilities (LEND) programs across the United States address today's health care shortages by providing comprehensive, interdisciplinary training to providers from multiple pediatric disciplines who screen, diagnose, and treat those with ASD and DD. Each LEND program develops training methods independently, including quality improvement efforts. In 2014, LEND programs began designing and validating common measures to evaluate LEND training. The LEND Program Quality Improvement (LPQI) Network was established in 2016. Participating LEND programs in the LPQI Network administer validated trainee self-report and faculty-observation measures that address skills in key competency domains of Interdisciplinary or Interprofessional Team Building, Family-Professional Partnerships, and Policy. This study reports data from faculty and trainees from 22 LEND programs that participated in the LPQI Network across the 5-year data collection period. The main outcome of this study was the change in trainee knowledge, skills, and attitudes scores in key competency domains across programs. Overall, trainees made significant knowledge, skills, and attitude gains based on both self-report and faculty observation scores for all 3 competency domains. Data demonstrate the value of LEND programs and feasibility of a national quality improvement approach to evaluate interdisciplinary training and systems-level improvement.

Medical Student Choices Regarding Ventilator Allocation for People With Disabilities.

In the COVID-19 pandemic, concerns exist that ventilator triage policies may lead to discrimination against people with disabilities. This study evaluates whether preclinical medical students demonstrate bias towards people with disabilities during an educational ventilator-allocation exercise. Written student responses to a triage simulation activity were analyzed to describe ventilator priority rankings and to identify themes regarding disability. Disability status was not cited as a reason to withhold a ventilator. Key themes observed in ventilator triage decisions included life expectancy, comorbidities, and social worth. Although disability discrimination has historically been perpetuated by health care professionals, it is encouraging that preclinical medical students did not demonstrate explicit bias against people with disabilities in ventilator triage scenarios.

Ethics Education in COVID-19: Preclinical Medical Students' Approach to Ventilator Allocation.

Introduction COVID-19 has confronted clinicians with a potential need to ration ventilators. There is little guidance for training medical students to make such decisions in future practice. How students would make ventilator triage decisions remains unknown. Methods One hundred fifty-three medical students in 18 problem-based learning groups participated in a ventilator-rationing exercise in April 2020 as part of an ethics curriculum adapted in response to the COVID-19 pandemic. Students were provided with a prompt requiring fictional patients to be prioritized for ventilators in the face of scarce resources. The authors reviewed group responses, tallied triage criteria, and identified approaches to triage decisions. Results The most common triage criteria were patient comorbidities, clinical status, age/life stage, prognosis, life expectancy, and an individual's role in pandemic response. Additional criteria included quality of life, ventilator availability, public perception, and patient need. Students approached triage decisions by developing systems for triage, appealing to empirical evidence and academic literature, making value judgments, and identifying adjuncts and alternatives to triage. Discussion With minimal input from educators, students learned key ethical principles in triage medicine, recapitulated approaches to triage described in the clinical and bioethics literature, and suggested methods for tolerating distress of complex ethical decisions. Medical education should equip students to critically consider bioethical concerns in triage and prepare for possible moral distress during public health crises.

Assessment of Disparities Associated With a Crisis Standards of Care Resource Allocation Algorithm for Patients in 2 US Hospitals During the COVID-19 Pandemic.

Importance: Significant concern has been raised that crisis standards of care policies aimed at guiding resource allocation may be biased against people based on race/ethnicity. Objective: To evaluate whether unanticipated disparities by race or ethnicity arise from a single institution's resource allocation policy. Design, Setting, and Participants: This cohort study included adults (aged ≥18 years) who were cared for on a coronavirus disease 2019 (COVID-19) ward or in a monitored unit requiring invasive or noninvasive ventilation or high-flow nasal cannula between May 26 and July 14, 2020, at 2 academic hospitals in Miami, Florida. Exposures: Race (ie, White, Black, Asian, multiracial) and ethnicity (ie, non-Hispanic, Hispanic). Main Outcomes and Measures: The primary outcome was based on a resource allocation priority score (range, 1-8, with 1 indicating highest and 8 indicating lowest priority) that was assigned daily based on both estimated short-term (using Sequential Organ Failure Assessment score) and longer-term (using comorbidities) mortality. There were 2 coprimary outcomes: maximum and minimum score for each patient over all eligible patient-days. Standard summary statistics were used to describe the cohort, and multivariable Poisson regression was used to identify associations of race and ethnicity with each outcome. Results: The cohort consisted of 5613 patient-days of data from 1127 patients (median [interquartile range {IQR}] age, 62.7 [51.7-73.7]; 607 [53.9%] men). Of these, 711 (63.1%) were White patients, 323 (28.7%) were Black patients, 8 (0.7%) were Asian patients, and 31 (2.8%) were multiracial patients; 480 (42.6%) were non-Hispanic patients, and 611 (54.2%) were Hispanic patients. The median (IQR) maximum priority score for the cohort was 3 (1-4); the median (IQR) minimum score was 2 (1-3). After adjustment, there was no association of race with maximum priority score using White patients as the reference group (Black patients: incidence rate ratio [IRR], 1.00; 95% CI, 0.89-1.12; Asian patients: IRR, 0.95; 95% CI. 0.62-1.45; multiracial patients: IRR, 0.93; 95% CI, 0.72-1.19) or of ethnicity using non-Hispanic patients as the reference group (Hispanic patients: IRR, 0.98; 95% CI, 0.88-1.10); similarly, no association was found with minimum score for race, again with White patients as the reference group (Black patients: IRR, 1.01; 95% CI, 0.90-1.14; Asian patients: IRR, 0.96; 95% CI, 0.62-1.49; multiracial patients: IRR, 0.81; 95% CI, 0.61-1.07) or ethnicity, again with non-Hispanic patients as the reference group (Hispanic patients: IRR, 1.00; 95% CI, 0.89-1.13). Conclusions and Relevance: In this cohort study of adult patients admitted to a COVID-19 unit at 2 US hospitals, there was no association of race or ethnicity with the priority score underpinning the resource allocation policy. Despite this finding, any policy to guide altered standards of care during a crisis should be monitored to ensure equitable distribution of resources.

COVID-19 Trial Enrollment for Those Who Cannot Consent: Ethical Challenges Posed by a Pandemic.

The current coronavirus disease 2019 (COVID-19) pandemic has triggered an intense global research effort to inform the life-saving work of frontline clinicians who need reliable information as soon as possible. Yet research done in pressured circumstances can lead to ethical dilemmas, especially for vulnerable research subjects. We present the case of a child with neurocognitive impairment who is diagnosed with COVID-19 infection after presenting with fever and a seizure. The child lives in a group home and is in the custody of the state; her parents lost parental rights many years ago. Some members of the health care team want to enroll her in a randomized clinical trial evaluating an experimental treatment of COVID-19. For minor patients to enroll in this clinical trial, the institutional review board requires assent of patients and consent of guardians. An ethics consult is called to help identify relevant concerns in enrollment. In the accompanying case discussion, we address historical perspectives on research involving people with disabilities; proper management of research participation for people with disabilities including consent by proxy, therapeutic misconception, and other threats to the ethical validity of clinical trials; and the potentially conflicting obligations of researchers and clinicians.

Whose Odyssey Is It? Family-Centered Care in the Genomic Era.

Despite a century of progress in medical knowledge, many diagnostic odysseys end in disappointment, especially when the child has a developmental disorder. In cases of autism and intellectual disability, relatively few children receive a specific diagnosis, and virtually none of those diagnoses lead to a specific medical treatment. Whole-genome or -exome sequencing offers a quantum leap in the diagnostic odyssey, in that we will always learn something from sequencing-sometimes much more than families bargained for, as discussed elsewhere in this special report. The trick is whether the knowledge gained will help the child and family. A family-centered approach gives families permission to choose but does not lay all of the responsibility on them. The goal is to pursue the degree of medical diagnostic evaluation that matches the family's values.