PEDIATRICS recent issues

The False-negative Phenotype

Ethical controversies may arise when genome sequencing reveals a genetic variant that is thought to be pathogenic, but the patient has no symptoms. This could be due to variable penetrance or expressivity. It could also result from a misclassification of the gene as pathogenic. In this article, I analyze 2 possibilities when such a situation occurs. The first is straightforward. We could conclude that the sequencing results should be considered a "false-positive" test result. The second is a bit more counterintuitive. In some cases, we could consider the test result to be a true-positive but in way that has not yet led to phenotypic findings. Somewhat playfully, we imagine that, in such cases, we could consider the patient’s phenotype to be falsely negative. Sometimes, as odd as it seems, we act is if that is what we believe.

Returning a Genomic Result for an Adult-Onset Condition to the Parents of a Newborn: Insights From the BabySeq Project

The return of information from genomic sequencing in children, especially in early life, brings up complex issues around parental autonomy, the child’s future autonomy, the best interest standard, and the best interests of the family. These issues are particularly important in considering the return of genomic results for adult-onset–only conditions in children. The BabySeq Project is a randomized trial used to explore the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of newborns who are healthy or sick. We discuss a case in which a variant in a gene for an actionable, adult-onset–only condition was detected, highlighting the ethical issues surrounding the return of such finding in a newborn to the newborn’s parents.

Physician Communication of Genomic Results in a Diagnostic Odyssey Case Series

BACKGROUND AND OBJECTIVES:

The availability of whole genome sequencing (WGS) is increasing in clinical care, and WGS is a promising tool in diagnostic odyssey cases. Physicians’ ability to effectively communicate genomic information with patients, however, is unclear. In this multiperspective study, we assessed physicians’ communication of patient genome sequencing information in a diagnostic odyssey case series.

METHODS:

We evaluated physician communication of genome sequencing results in the context of an ongoing study of the utility of WGS for the diagnosis of rare and idiopathic diseases. A modified version of the Medical Communication Competence Scale was used to compare patients’ ratings of their physicians’ communication of general medical information to communication of genome sequencing information. Physician self-ratings were also compared with patient ratings.

RESULTS:

A total of 47 patients, parents, and physicians across 11 diagnostic odyssey cases participated. In 6 of 11 cases (54%), the patient respondent rated the physician’s communication of genome sequencing information as worse than that of general medical information. In 9 of 11 cases (82%), physician self-ratings of communication of genome sequencing information were worse than the patient respondent’s rating. Identification of a diagnosis via WGS was positively associated with physician self-ratings (P = .021) but was not associated with patient respondent ratings (P = .959).

CONCLUSIONS:

These findings reveal that even in diagnostic odyssey cases, in which genome sequencing may be clinically beneficial, physicians may not be well-equipped to communicate genomic information to patients. Future studies may benefit from multiperspective approaches to assessing and understanding physician-patient communication of genome-sequencing information.

Neonatologists Attitudes About Diagnostic Whole-Genome Sequencing in the NICU

Using focus group methodology, we studied the attitudes of neonatologists regarding diagnostic rapid genome sequencing for newborns who were critically ill in a NICU. One focus group took place within the first year after whole-genome sequencing testing became available, and another focus group took place 3 years later. Focus groups were audiotaped, transcribed, and analyzed by using standard techniques of grounded theory. Different analysts coded them for themes. The analysts then discussed differences and agreed on major themes. Twelve doctors participated in the first focus group, and 9 doctors participated in the second; 62% were attending physicians, and the rest were fellows. There were 14 women and 7 men. We did not collect any other demographic information on participants. Surprisingly, we found few differences between the earlier focus group and the later one. Comments were categorized as falling into 4 domains: (1) uncertainty about the interpretation of results, (2) issues about parental consent and limits on their right to know genomic information, (3) different opinions about whether and how genomic results could be clinically useful, and (4) potential harms of genomic testing.

Child BMI Over Time and Parent-Perceived Overweight

BACKGROUND AND OBJECTIVES:

Parents often do not accurately perceive overweight and/or obesity in their children. Changing this is widely considered an essential first step to reducing child overweight, but recent research suggests that, in fact, this could promote greater weight gain. We aimed to determine the directionality over time between higher child adiposity and parental perception of child overweight.

METHODS:

Participants were from 2 cohorts of the population-based Longitudinal Study of Australian Children followed biennially since 2004. Repeated measures of BMI z scores and parental perceptions of overweight were available for the kindergarten cohort at 6 waves (ages 4–5, 6–7, 8–9, 10–11, 12–13, and 14–15 years; n = 4632) and for the birth cohort at 4 waves (ages 2–3, 4–5, 8–9, and 10–11 years; n = 4445). Bidirectionality between overweight perception and BMI z score was examined by using cross-lagged regression models.

RESULTS:

In both cohorts, wave-on-wave lagged effects were strong (all: P < .001) but much larger from BMI z score to parent perception. For every unit increase in the BMI z score, the odds of a child being perceived as overweight in the next wave ranged from 2.9 (birth cohort: age 2–3 years) to 10.4 (kindergarten cohort: age 6–7 years). These effects were ~3 to 12 times larger than the reverse, whereby the perception of overweight predicted 0.2 to 0.5 higher BMI z score in the next wave.

CONCLUSIONS:

Higher child BMI z scores strikingly predicted a subsequent parental perception of child overweight. Parent-perceived overweight preceded rising (not falling) BMI, but these effects were small. Clinician efforts to make parents aware of overweight may not be harmful but seem unlikely to improve children’s BMI status.

The Prevalence of Parent-Reported Autism Spectrum Disorder Among US Children

OBJECTIVES:

To estimate the national prevalence of parent-reported autism spectrum disorder (ASD) diagnosis among US children aged 3 to 17 years as well as their treatment and health care experiences using the 2016 National Survey of Children’s Health (NSCH).

METHODS:

The 2016 NSCH is a nationally representative survey of 50 212 children focused on the health and well-being of children aged 0 to 17 years. The NSCH collected parent-reported information on whether children ever received an ASD diagnosis by a care provider, current ASD status, health care use, access and challenges, and methods of treatment. We calculated weighted prevalence estimates of ASD, compared health care experiences of children with ASD to other children, and examined factors associated with increased likelihood of medication and behavioral treatment.

RESULTS:

Parents of an estimated 1.5 million US children aged 3 to 17 years (2.50%) reported that their child had ever received an ASD diagnosis and currently had the condition. Children with parent-reported ASD diagnosis were more likely to have greater health care needs and difficulties accessing health care than children with other emotional or behavioral disorders (attention-deficit/hyperactivity disorder, anxiety, behavioral or conduct problems, depression, developmental delay, Down syndrome, intellectual disability, learning disability, Tourette syndrome) and children without these conditions. Of children with current ASD, 27% were taking medication for ASD-related symptoms, whereas 64% received behavioral treatments in the last 12 months, with variations by sociodemographic characteristics and co-occurring conditions.

CONCLUSIONS:

The estimated prevalence of US children with a parent-reported ASD diagnosis is now 1 in 40, with rates of ASD-specific treatment usage varying by children’s sociodemographic and co-occurring conditions.

Neurodevelopmental Outcomes in Infants With Birth Weight <=500 g at 3 Years of Age

OBJECTIVES:

To determine neurodevelopmental outcomes at 3 years of age in children born with a birth weight (BW) of ≤500 g.

METHODS:

Infants who were born with a BW of ≤500 g from 2003 to 2012 in the Neonatal Research Network of Japan and survived to discharge from the NICU were eligible in this study. The study population consisted of 460 children (56.7% of 811 surviving infants) who were evaluated at 36 to 42 months of age. Neurodevelopmental impairment (NDI) was defined as having cerebral palsy, visual impairment, hearing impairment, or a developmental quotient score of <70.

RESULTS:

The overall proportion of NDI was 59.1% (95% confidence interval [CI]: 54.6%–63.5%). The trend revealed no significant change during the study period. In a multivariate modified Poisson regression analysis, NDI was associated with severe intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95% CI: 1.19–1.68; P < .01), cystic periventricular leukomalacia (adjusted RR: 1.40; 95% CI: 1.13–1.73; P < .01), severe necrotizing enterocolitis (adjusted RR: 1.31; 95% CI: 1.07–1.60; P < .01), surgical ligation for patent ductus arteriosus (adjusted RR: 1.29; 95% CI: 1.09–1.54; P < .01), and male sex (adjusted RR: 1.19; 95% CI: 1.01–2.40; P = .04).

CONCLUSIONS:

This cohort showed that neurodevelopmental outcomes of infants with a BW of ≤500 g have not improved from 2003 to 2012. Multivariate analysis revealed that severe intracranial hemorrhage and cystic periventricular leukomalacia were the strongest risk factors for NDIs. Our data suggested that measures aimed at reducing neurologic morbidities will be important for improving outcomes of infants with a BW of ≤500 g.

Adherence of Newborn-Specific Antibiotic Stewardship Programs to CDC Recommendations

BACKGROUND:

The Centers for Disease Control and Prevention (CDC) published the Core Elements of Hospital Antibiotic Stewardship Programs (ASPs), while the Choosing Wisely for Newborn Medicine Top 5 list identified antibiotic therapy as an area of overuse. We identify the baseline prevalence and makeup of newborn-specific ASPs and assess the variability of NICU antibiotic use rates (AURs).

METHODS:

Data were collected using a cross-sectional audit of Vermont Oxford Network members in February 2016. Unit measures were derived from the 7 domains of the CDC’s Core Elements of Hospital ASPs, including leadership commitment, accountability, drug expertise, action, tracking, reporting, and education. Patient-level measures included patient demographics, indications, and reasons for therapy. An AUR, defined as the number of infants who are on antibiotic therapy divided by the census that day, was calculated for each unit.

RESULTS:

Overall, 143 centers completed structured self-assessments. No center addressed all 7 core elements. Of the 7, only accountability (55%) and drug expertise (62%) had compliance >50%. Centers audited 4127 infants for current antibiotic exposure. There were 725 infants who received antibiotics, for a hospital median AUR of 17% (interquartile range 10%–26%). Of the 412 patients on >48 hours of antibiotics, only 26% (107 out of 412) had positive culture results.

CONCLUSIONS:

Significant gaps exist between CDC recommendations to improve antibiotic use and antibiotic practices during the newborn period. There is wide variation in point prevalence AURs. Three-quarters of infants who received antibiotics for >48 hours did not have infections proven by using cultures.

Uninterrupted Infant Sleep, Development, and Maternal Mood

OBJECTIVES:

Contrary to the importance of total sleep duration, the association between sleeping through the night and development in early infancy remains unclear. Our aims were to investigate the proportion of infants who sleep through the night (6- or 8-hour sleep blocks) at ages 6 and 12 months in a longitudinal cohort and to explore associations between sleeping through the night, mental and psychomotor development, maternal mood, and breastfeeding.

METHODS:

At 6 and 12 months of age, maternal reports were used to assess the longest period of uninterrupted infant sleep and feeding method (n = 388). Two different criteria were used to determine if infants slept through the night: 6 and 8 hours of uninterrupted sleep. Mental and psychomotor developmental indices (Bayley Scales of Infant Development II) and maternal mood (Center for Epidemiologic Studies Depression Scale) were measured at 6, 12, and 36 months of age.

RESULTS:

Using a definition of either 6 or 8 hours of uninterrupted sleep, we found that 27.9% to 57.0% of 6- and 12-month-old infants did not sleep through the night. Linear regressions revealed no significant associations between sleeping through the night and concurrent or later mental development, psychomotor development, or maternal mood (P > .05). However, sleeping through the night was associated with a much lower rate of breastfeeding (P < .0001).

CONCLUSIONS:

Considering that high proportions of infants did not sleep through the night and that no associations were found between uninterrupted sleep, mental or psychomotor development, and maternal mood, expectations for early sleep consolidation could be moderated.

Early Antibiotic Exposure and Weight Outcomes in Young Children

OBJECTIVES:

To determine the association of antibiotic use with weight outcomes in a large cohort of children.

METHODS:

Health care data were available from 2009 to 2016 for 35 institutions participating in the National Patient-Centered Clinical Research Network. Participant inclusion required same-day height and weight measurements at 0 to <12, 12 to <30, and 48 to <72 months of age. We assessed the association between any antibiotic use at <24 months of age with BMI z score and overweight or obesity prevalence at 48 to <72 months (5 years) of age, with secondary assessments of antibiotic spectrum and age-period exposures. We included children with and without complex chronic conditions.

RESULTS:

Among 1 792 849 children with a same-day height and weight measurement at <12 months of age, 362 550 were eligible for the cohort. One-half of children (52%) were boys, 27% were African American, 18% were Hispanic, and 58% received ≥1 antibiotic prescription at <24 months of age. At 5 years, the mean BMI z score was 0.40 (SD 1.19), and 28% of children had overweight or obesity. In adjusted models for children without a complex chronic condition at 5 years, we estimated a higher mean BMI z score by 0.04 (95% confidence interval [CI] 0.03 to 0.05) and higher odds of overweight or obesity (odds ratio 1.05; 95% CI 1.03 to 1.07) associated with obtaining any (versus no) antibiotics at <24 months.

CONCLUSIONS:

Antibiotic use at <24 months of age was associated with a slightly higher body weight at 5 years of age.

Online Family Problem-solving Treatment for Pediatric Traumatic Brain Injury

BACKGROUND AND OBJECTIVES:

To determine whether online family problem-solving treatment (OFPST) is more effective in improving behavioral outcomes after pediatric traumatic brain injury with increasing time since injury.

METHODS:

This was an individual participant data meta-analysis of outcome data from 5 randomized controlled trials of OFPST conducted between 2003 and 2016. We included 359 children ages 5 to 18 years who were hospitalized for moderate-to-severe traumatic brain injury 1 to 24 months earlier. Outcomes, assessed pre- and posttreatment, included parent-reported measures of externalizing, internalizing, and executive function behaviors and social competence.

RESULTS:

Participants included 231 boys and 128 girls with an average age at injury of 13.6 years. Time since injury and age at injury moderated OFPST efficacy. For earlier ages and short time since injury, control participants demonstrated better externalizing problem scores than those receiving OFPST (Cohen’s d = 0.44; P = .008; n = 295), whereas at older ages and longer time since injury, children receiving OFPST had better scores (Cohen’s d = –0.60; P = .002). Children receiving OFPST were rated as having better executive functioning relative to control participants at a later age at injury, with greater effects seen at longer (Cohen’s d = –0.66; P = .009; n = 298) than shorter (Cohen’s d = –0. 28; P = .028) time since injury.

CONCLUSIONS:

OFPST may be more beneficial for older children and when begun after the initial months postinjury. With these findings, we shed light on the optimal application of family problem-solving treatments within the first 2 years after injury.

Child Abuse, Incarceration, and Decisions About Life-sustaining Treatment

Most critical care interventions for children occur in the framework of a supportive environment with loving parents that are present at the bedside to help to guide medical interventions through shared decision-making. What happens, however, if the parents are precluded from being at the bedside because of legal entanglements? How should clinical decisions progress in those cases? In this Ethics Rounds, we present the case of an infant with severe hypoxic-ischemic encephalopathy at birth whose mother was incarcerated shortly after delivery. We explore clinical and legal challenges that the medical team faces in determining best interests for the infant in this context and difficulties in deciding what therapies to provide and for how long.

When Parents Have Misunderstandings About the Risks and Benefits of Palliative Surgery

When a child needs surgery, both the surgeon and the anesthesiologist must obtain informed consent from the parents. In theory, each specialist obtains permission for their respective portion of the procedure, with the anesthesiologist only obtaining informed consent for the administration of anesthesia and management in the operating room and recovery room. However, he or she may occasionally realize that the parents have misunderstandings about what the surgery and perioperative course entail. In such cases, he or she must decide whether their role is only to discuss the issues related to anesthesia care or whether he or she should also clarify the range of expected outcomes and the postoperative course after surgery. We present a case in which such a dilemma arose and on which we sought experts in anesthesia and ethics to comment.

E-cigarette Use and Subsequent Smoking Frequency Among Adolescents

BACKGROUND AND OBJECTIVES:

Electronic cigarette (e-cigarette) use is associated with cigarette initiation among adolescents. However, it is unclear whether e-cigarette use is associated with more frequent cigarette use after initiation. Also, the extent to which cigarette or dual cigarette and e-cigarette users transition to exclusive e-cigarette use or to the nonuse of either product is not yet known.

METHODS:

Data were pooled from 3 prospective cohort studies in California and Connecticut (baseline: 2013–2014; follow-up: 2014–2016; N = 6258). Polytomous regression models were used to evaluate the association of baseline e-cigarette use (never or ever) with cigarette use frequency at follow-up (experimental: initiation but no past-30-day use; infrequent: 1–2 of the past 30 days; frequent: 3–5 or more of the past 30 days). Polytomous regression models were also used to evaluate transitions between baseline ever or past-30-day single or dual product use and past-30-day single or dual product use at follow-up.

RESULTS:

Among baseline never smokers, e-cigarette users had greater odds of subsequent experimental (odds ratio [OR] = 4.58; 95% confidence interval [CI]: 3.56–5.88), infrequent (OR = 4.27; 95% CI: 2.75–6.62) or frequent (OR = 3.51; 95% CI: 1.97–6.24) cigarette use; the 3 OR estimates were not significantly different. Baseline past-30-day exclusive cigarette use was associated with higher odds at follow-up of exclusive cigarette or dual product use than of exclusive e-cigarette use.

CONCLUSIONS:

Tobacco control policy to reduce adolescent use of both e-cigarettes and cigarettes is needed to prevent progression to more frequent tobacco use patterns and reduce combustible cigarette use (with or without concurrent e-cigarette use) to lessen the adverse public health impact of e-cigarettes.

Diagnosis of Attenuated Mucopolysaccharidosis VI: Clinical, Biochemical, and Genetic Pitfalls

Mucopolysaccharidosis type VI (MPS VI) is a clinically heterogeneous lysosomal disease, which can be divided into 2 main categories on the basis of age of onset and severity of symptoms. The diagnosis of the attenuated form is often delayed given subtle facial features rather than the typical coarse facial features of the classic form. Here, we discuss the difficulties in establishing the diagnosis of MPS VI on the basis of the report of 4 individuals. The most common signs and symptoms in our series were bone abnormalities and hip pain as initial manifestations and cardiac changes detected after follow-up studies. On the basis of our cohort and others worldwide, awareness of attenuated forms of MPS VI should be increased particularly among general practitioners, pediatricians, rheumatologists, orthopedists, ophthalmologists, and cardiologists. Moreover, these health care providers should be aware of the technical aspects involved in the molecular and biochemical diagnosis process so that they are aware how diagnostic errors may occur.

Improving Timeliness of Medical Evaluations for Children Entering Foster Care

BACKGROUND AND OBJECTIVES:

The American Academy of Pediatrics (AAP) recommends children in foster care (FC) have an initial medical evaluation within 3 days of custody initiation; however, this vulnerable population often suffers from disjointed care. Our aim was to improve the mean time to initial foster care evaluation (TIE) from 32 to <7 days within 12 months for children in FC in Durham County, North Carolina.

METHODS:

This study was a time series, quality improvement project used to target interventions within an academic clinic and a community agency. Interventions were tested through multiple plan-do-study-act cycles. Control charts of the primary outcome, the TIE, were constructed. Charts were annotated with the dates of interventions, including workshops, performance feedback, integration of state forms, identification of appointments, development of an urgent appointment pathway, and empowerment of the scheduler.

RESULTS:

The mean TIE improved from 32 to 9 days within 12 months. Significant improvement in the following 2 process measures contributed to this: the time from custody initiation to the referral date improved from an average of 10 to 3 days, and the time from referral date to the initial evaluation improved from an average of 22 to 6 days.

CONCLUSIONS:

Improvement interventions and increased collaboration between medical and child welfare agencies can result in significant improvement of the TIE. However, despite improvement efforts, challenges remain in meeting the AAP 3-day TIE recommendation. We recommend further assessment of the AAP guideline as it relates to implementation feasibility and health outcomes of children in FC.

Marijuana and Tobacco Coexposure in Hospitalized Children

BACKGROUND:

The impact of secondhand marijuana smoke exposure on children is unknown. New methods allow for the detection of marijuana smoke exposure in children.

METHODS:

We studied children who were hospitalized in Colorado and had a parent participating in a smoking cessation study; all children had urine samples remaining from the original study as well as consent for future research. Parents completed a survey and urine samples were analyzed for cotinine and marijuana metabolites, including 11-hydroxy-9-tetrahydrocannabinol (COOH-THC), by using liquid chromatography-tandem mass spectrometry.

RESULTS:

The median age of the children was 6.0 years (range 0–17 years); 57% were boys. Half (55%) were white, 12% were African American, and 33% were of another race; 39% identified as Hispanic. Approximately 46% had detectable COOH-THC, and 11% had detectable THC. Of those with detectable THC, 3 were teenagers, and 6 were <8 years of age. There were no significant differences in urinary COOH-THC concentrations by age, sex, race and/or ethnicity, or socioeconomic status. Children with positive results for COOH-THC were more likely to have parents who use marijuana daily, smoke marijuana versus other forms of use, use daily in the home, and smoke marijuana in another room if the children are around compared with smoking outside.

CONCLUSIONS:

Approximately half of the children who qualified for our study had biological evidence of exposure to marijuana. Researchers in studies such as this provide valuable data on secondhand exposure to children from parents using tobacco and marijuana and can inform public health policies to reduce harm.

A Prediction Model to Determine Childhood Epilepsy After 1 or More Paroxysmal Events

OBJECTIVES:

The clinical profile of children who had possible seizures is heterogeneous, and accuracy of diagnostic testing is limited. We aimed to develop and validate a prediction model that determines the risk of childhood epilepsy by combining available information at first consultation.

METHODS:

We retrospectively collected data of 451 children who visited our outpatient department for diagnostic workup related to 1 or more paroxysmal event(s). At least 1 year of follow-up was available for all children who were diagnosed with epilepsy or in whom diagnosis remained inconclusive. Clinical characteristics (sex, age of first seizure, event description, medical history) and EEG report were used as predictor variables for building a multivariate logistic regression model. Performance was validated in an external cohort (n = 187).

RESULTS:

Model discrimination was excellent, with an area under the receiver operating characteristic curve of 0.86 (95% confidence interval [CI]; 0.80–0.92), a positive predictive value of 0.93 (95% CI 0.83–0.97) and a negative predictive value of 0.76 (95% CI 0.70–0.80). Model discrimination in a selective subpopulation of children with uncertain diagnosis after initial clinical workup was good, with an area under the receiver operating characteristic curve of 0.73 (95% CI 0.58–0.87).

CONCLUSIONS:

This model may prove to be valuable because predictor variables together with a first interictal EEG can be available at first consultation. A Web application is provided (http://epilepsypredictiontools.info/first-consultation) to facilitate the diagnostic process for clinicians who are confronted with children with paroxysmal events, suspected of having an epileptic origin.

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