Beyond linearity in neuroimaging: Capturing nonlinear relationships with application to longitudinal studies.

The ubiquitous adoption of linearity for quantitative predictors in statistical modeling is likely attributable to its advantages of straightforward interpretation and computational feasibility. The linearity assumption may be a reasonable approximation especially when the variable is confined within a narrow range, but it can be problematic when the variable's effect is non-monotonic or complex. Furthermore, visualization and model assessment of a linear fit are usually omitted because of challenges at the whole brain level in neuroimaging. By adopting a principle of learning from the data in the presence of uncertainty to resolve the problematic aspects of conventional polynomial fitting, we introduce a flexible and adaptive approach of multilevel smoothing splines (MSS) to capture any nonlinearity of a quantitative predictor for population-level neuroimaging data analysis. With no prior knowledge regarding the underlying relationship other than a parsimonious assumption about the extent of smoothness (e.g., no sharp corners), we express the unknown relationship with a sufficient number of smoothing splines and use the data to adaptively determine the specifics of the nonlinearity. In addition to introducing the theoretical framework of MSS as an efficient approach with a counterbalance between flexibility and stability, we strive to (a) lay out the specific schemes for population-level nonlinear analyses that may involve task (e.g., contrasting conditions) and subject-grouping (e.g., patients vs controls) factors; (b) provide modeling accommodations to adaptively reveal, estimate and compare any nonlinear effects of a predictor across the brain, or to more accurately account for the effects (including nonlinear effects) of a quantitative confound; (c) offer the associated program 3dMSS to the neuroimaging community for whole-brain voxel-wise analysis as part of the AFNI suite; and (d) demonstrate the modeling approach and visualization processes with a longitudinal dataset of structural MRI scans.

The NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty: Protocol and rationale for methods and measures.

Delineating the relationship between human neurodevelopment and the maturation of the hypothalamic-pituitary-gonadal (HPG) axis during puberty is critical for investigating the increase in vulnerability to neuropsychiatric disorders that is well documented during this period. Preclinical research demonstrates a clear association between gonadal production of sex steroids and neurodevelopment; however, identifying similar associations in humans has been complicated by confounding variables (such as age) and the coactivation of two additional endocrine systems (the adrenal androgenic system and the somatotropic growth axis) and requires further elucidation. In this paper, we present the design of, and preliminary observations from, the ongoing NIMH Intramural Longitudinal Study of the Endocrine and Neurobiological Events Accompanying Puberty. The aim of this study is to directly examine how the increase in sex steroid hormone production following activation of the HPG-axis (i.e., gonadarche) impacts neurodevelopment, and, additionally, to determine how gonadal development and maturation is associated with longitudinal changes in brain structure and function in boys and girls. To disentangle the effects of sex steroids from those of age and other endocrine events on brain development, our study design includes 1) selection criteria that establish a well-characterized baseline cohort of healthy 8-year-old children prior to the onset of puberty (e.g., prior to puberty-related sex steroid hormone production); 2) temporally dense longitudinal, repeated-measures sampling of typically developing children at 8-10 month intervals over a 10-year period between the ages of eight and 18; 3) contemporaneous collection of endocrine and other measures of gonadal, adrenal, and growth axis function at each timepoint; and 4) collection of multimodal neuroimaging measures at these same timepoints, including brain structure (gray and white matter volume, cortical thickness and area, white matter integrity, myelination) and function (reward processing, emotional processing, inhibition/impulsivity, working memory, resting-state network connectivity, regional cerebral blood flow). This report of our ongoing longitudinal study 1) provides a comprehensive review of the endocrine events of puberty; 2) details our overall study design; 3) presents our selection criteria for study entry (e.g., well-characterized prepubertal baseline) along with the endocrinological considerations and guiding principles that underlie these criteria; 4) describes our longitudinal outcome measures and how they specifically relate to investigating the effects of gonadal development on brain development; and 5) documents patterns of fMRI activation and resting-state networks from an early, representative subsample of our cohort of prepubertal 8-year-old children.

A pilot study on pediatric mononucleosis presenting with abscess.

CONTEXT: To describe this new clinical entity, diagnosis, and potential management of pediatric intratonsillar/peritonsillar abscesses in children affected by infectious mononucleosis. METHODS: After institutional review board approval, a retrospective chart review of patients who underwent testing for infectious mononucleosis and also had a computed tomography scan of the head and neck was completed. Those who did not have imaging showing the palatine tonsils and those with insufficient testing to diagnose infectious mononucleosis were excluded. MAIN FINDINGS: One hundred patients were included in the study; 15 had a peritonsillar abscess and 29 had an intratonsillar abscess. Four of the patients with a peritonsillar abscess (26.7%) had a positive Monospot or Epstein-Barr virus IgM result, and two of 15 (13.3%) had positive rapid strep or culture results. Of the 29 patients with an intratonsillar abscess, eight (27.6%) had a positive Monospot or Epstein-Barr virus IgM result while two (6.9%) had a positive rapid strep or culture result. Of those with bilateral intratonsillar abscess, five of 12 (41.7%) patients showed laboratory markers for infectious mononucleosis compared with three of 17 (17.6%) with unilateral intratonsillar abscess. This difference was not statistically significant (Fischer's, p = 0.218). CONCLUSION: In our cohort of patients undergoing computed tomography scan and acute infectious mononucleosis testing, patients with intratonsillar and peritonsillar abscess tested positive for mononucleosis markers more commonly than for streptococcus markers. Recognizing uncomplicated intratonsillar and peritonsillar abscess in the setting of infectious mononucleosis in these pediatric patients may help tailor management in this population.

Communications, engagement, and dissemination strategies for the HEALthy Brain and Child Development (HBCD) Study.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Study success depends on the engagement and inclusion of diverse populations of pregnant participants and their children across the United States, including those at high and low risk for prenatal substance use. The Communications, Engagement, and Dissemination (CED) Committee is responsible for the development and implementation of a strategy to promote awareness about the study, encourage participation, and engage HBCD families, community partners, and collaborators. Initial work involved developing versatile recruitment and awareness materials with a consistent and inclusive message that reduces stigma and negative bias towards marginalized populations, including people with substance use and other mental health conditions. These efforts were shaped by an integrated product development workflow and early engagement with HBCD partners to address challenges. Ongoing work includes the expansion of HBCD outreach through newsletters and social media platforms with an emphasis on protecting participant privacy. Future activities will focus on disseminating scientific information through generation of infographics and webinars that will inform participants, families, and the public of discoveries generated from HBCD Study data.

Assessing prenatal and early childhood social and environmental determinants of health in the HEALthy Brain and Child Development Study (HBCD).

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The charge of the HBCD Social and Environmental Determinants (SED) working group is to develop and implement a battery of assessments to broadly characterize the social and physical environment during the prenatal period and early life to characterize risk and resilience exposures that can impact child growth and development. The SED battery consists largely of measures that will be repeated across the course of the HBCD Study with appropriate modifications for the age of the child and include participant demographics, indicators of socioeconomic status, stress and economic hardship, bias and discrimination (e.g., racism), acculturation, neighborhood safety, child and maternal exposures to adversity, environmental toxicants, social support, and other protective factors. Special considerations were paid to reducing participant burden, promoting diversity, equity, and inclusion, and adopting trauma-informed practices for the collection of sensitive information such as domestic violence exposure and adverse childhood experiences. Overall, the SED battery will provide essential data to advance understanding of child development and approaches to advance health equity across infant and child development.

Advancing high quality longitudinal data collection: Implications for the HEALthy Brain and Child Development (HBCD) Study design and recruitment.

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The HBCD Study aims to reflect the sociodemographic diversity of pregnant individuals in the U.S. The study will also oversample individuals who use substances during pregnancy and enroll similar individuals who do not use to allow for generalizable inferences of the impact of prenatal substance use on trajectories of child development. Without probability sampling or a randomization-based design, the study requires innovation during enrollment, close monitoring of group differences, and rigorous evaluation of external and internal validity across the enrollment period. In this article, we discuss the HBCD Study recruitment and enrollment data collection processes and potential analytic strategies to account for sources of heterogeneity and potential bias. First, we introduce the adaptive design and enrollment monitoring indices to assess and enhance external and internal validity. Second, we describe the visit schedule for in-person and remote data collection where dyads are randomly assigned to visit windows based on a jittered design to optimize longitudinal trajectory estimation. Lastly, we provide an overview of analytic procedures planned for estimating trajectories.

Altered pubertal timing in 7q11.23 copy number variations and associated genetic mechanisms.

Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R2 = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS < TD < Dup7; p = 1.2x10-8, η2 = 0.45) and pituitary volume (WS < TD < Dup7; p = 3x10-5, ηp2 = 0.2) with greater effect sizes. Finally, we relate an AAM-GWAS signal in 7q11.23 to altered expression in postmortem brains of STAG3L2 (p = 1.7x10-17), a gene we also find differentially expressed with 7q11.23 copy number (p = 0.03). Collectively, these data explicate the role of 7q11.23 in pubertal onset, with STAG3L2 and pituitary development as potential mediators.

The HEALthy Brain and Child Development Study (HBCD): NIH collaboration to understand the impacts of prenatal and early life experiences on brain development.

The human brain undergoes rapid development during the first years of life. Beginning in utero, a wide array of biological, social, and environmental factors can have lasting impacts on brain structure and function. To understand how prenatal and early life experiences alter neurodevelopmental trajectories and shape health outcomes, several NIH Institutes, Centers, and Offices collaborated to support and launch the HEALthy Brain and Child Development (HBCD) Study. The HBCD Study is a multi-site prospective longitudinal cohort study, that will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. Influenced by the success of the ongoing Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®) and in partnership with the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, the HBCD Study aims to establish a diverse cohort of over 7000 pregnant participants to understand how early life experiences, including prenatal exposure to addictive substances and adverse social environments as well as their interactions with an individual's genes, can affect neurodevelopmental trajectories and outcomes. Knowledge gained from the HBCD Study will help identify targets for early interventions and inform policies that promote resilience and mitigate the neurodevelopmental effects of adverse childhood experiences and environments.

Current Pediatric Tertiary Care Admission Practices Following Adenotonsillectomy.

IMPORTANCE: Pediatric adenotonsillectomy is a frequently performed procedure. Few studies have examined perioperative practice patterns for children undergoing adenotonsillectomy. OBJECTIVE: To assess current group practice patterns associated with the perioperative care of children undergoing adenotonsillectomy for sleep-disordered breathing at tertiary care children's hospitals following the release of the 2011 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guidelines. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey was distributed to the chiefs of 72 pediatric otolaryngology divisions at tertiary care children's hospitals in the United States and Canada from March 25 to April 16, 2014. MAIN OUTCOMES AND MEASURES: Internet-based survey responses from the chiefs of pediatric otolaryngology at tertiary care children's hospitals in the United States and Canada, who responded regarding group, rather than individual, practices. RESULTS: Of the 72 surveys sent, 48 responses (67%) were received. Twenty-one respondents (44%) reported that their group has no official admission policy for children with sleep-disordered breathing. Seventy-three percent (29 of 40) reported using some measure of obesity as a criterion for postoperative admission. The AAO-HNS polysomnography criteria for severe obstructive sleep apnea were used by 40% of respondents (16 of 40) as admission criteria, whereas 15% (6 of 40) used the American Academy of Pediatrics criteria for severe obstructive sleep apnea. Seventy-three percent (29 of 40) reported requiring a child to be asleep while breathing room air without oxygen desaturation before discharge to home. An established minimum time for observation was reported by 43 of the respondents (90%). Institution size or volume of adenotonsillectomies performed did not affect the results. CONCLUSIONS AND RELEVANCE: Many tertiary care children's hospitals in the United States do not have an official admission policy to guide adenotonsillectomy care. Even for institutions that do have an official admission policy, the policies are not universally aligned with the AAO-HNS clinical practice guidelines. These survey results demonstrate an opportunity to improve quality and safety regarding admission policy practice patterns after pediatric adenotonsillectomy.

Outcomes of recalcitrant idiopathic epistaxis in children: Septoplasty as a surgical treatment.

Our objective was to measure short- and long-term outcomes of children presenting with recalcitrant idiopathic epistaxis. The study was an 11-year (2000-2011) retrospective chart review of children evaluated and treated for epistaxis. A retrospective review of patients with diagnostic International Classification of Diseases, Ninth Revision code 784.7 (epistaxis) and 21.5/21.88 (septoplasty) was completed reviewing age at presentation, type of surgery, and number of bleeding events prior to and after surgery. In our cohort, almost 100% of children with idiopathic recurrent epistaxis responded to topical treatments. About 0.2% were refractory (20/9239), and 90% of those (18/20) resolved with either a traditional septoplasty (14/20) or modified septoplasty (6/20) without cartilage excision, with a mean follow-up of 35 months. One of the patients who did not show resolution was found to have Von Willebrand disease, which likely contributed to this outcome. Septoplasty surgery, with or without cartilage removal, appears beneficial for refractory idiopathic epistaxis in children. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2833-2837, 2016.