Strengthening the evidence to improve health outcomes of children with perinatal HIV exposure.

INTRODUCTION: The number of children exposed to HIV and possibly to antiretroviral therapy (ART) in utero and during breastfeeding and are uninfected (HEU) globally will continue to increase from the estimated 15.9 million in 2021. DISCUSSION: There are still significant gaps in our understanding of the impact of HIV and/or ART exposure in children who are HEU, in terms of prevalence/incidence and severity on health and wellbeing, and long after exposure has ended. While there have been substantial programmatic efforts to support the elimination of vertical transmission of HIV, additional rigorous research is needed to better understand the biological, (psycho)social and structural factors contributing to optimal health for populations who are HEU. Furthermore, the best approaches to address and study the gaps in understanding also need to be explored. Given the scope of the problem including the large numbers of affected people as well as the often limited and competing in-country resources for populations affected by HIV, novel methodologies, including multi-level approaches and advanced analytics, need to be considered. CONCLUSIONS: A growing population of children who are HEU are maturing into adolescence and young adulthood. Research to advance understanding of the possible negative long-term effects of HIV and/or ART exposure in these youth is supported by the US National Institutes of Health. Both large epidemiological studies and smaller more comprehensive cohort studies may be required to address the complexity of the issue. Integrating both types of studies could allow the establishment of more reliable and validated predictions of which youth who are HEU are at the highest risk for specific negative health outcomes, such as mental health and neurocognitive disorders, and which interventional approaches may be most successful to address specific deficits both in terms of prevention and treatment. Finally, these goals can be more rapidly achieved with data science efforts, data harmonisation between studies and with sustainable data-sharing practices. It is important to expand the commitment to research to identify biological, social and structural drivers, to develop screening tools, and impactful and contextually appropriate interventions to address the health and wellbeing of children who are HEU from birth through adulthood.

Biotypes of Central Nervous System Complications in People Living With Human Immunodeficiency Virus (HIV): National Institute of Mental Health Perspectives on Advancing the Future of HIV Healthcare.

Despite effective suppressive antiretroviral therapy, central nervous system (CNS) complications related to human immunodeficiency virus (HIV) remain a significant problem for people with HIV (PWH). Numerous studies have contributed data to define the mechanisms underlying HIV-associated CNS pathophysiology, but causality remains elusive, with no effective therapies to prevent, reduce, or reverse HIV-associated CNS complications. Multiple physiological, clinical, cognitive, behavioral, social, and environmental factors contribute to the observed heterogeneity of adverse CNS outcomes among PWH. The National Institute of Mental Health in collaboration with investigators engaged in research related to HIV associated CNS complications organized a series of meetings to review the state of the science and facilitate the development of biologically based measures to identify the phenotypic heterogeneity of CNS outcomes linked to pathophysiology (biotypes). In this article, we summarize the proceedings of these meetings and explore the precision medicine framework to identify critical factors linked to the etiopathogenesis of CNS outcomes in PWH.

Prescription Psychoactive Medication Use in Adolescent Survivors of Childhood Cancer and Association With Adult Functional Outcomes.

BACKGROUND: This study estimates the prevalence and identifies predictors of psychoactive medication use in adolescent survivors of childhood cancer (aged 12-18 years) and its associations with functional outcomes at young adulthood (aged 18-28 years). METHODS: This retrospective cohort study includes 5665 adolescent survivors of childhood cancer at no less than 5 years postdiagnosis (53.8% male, median age = 15 years, interquartile range [IQR] = 13-16 years) and 921 adolescent sibling controls. Parent-reported psychoactive medication use during adolescence was collected at baseline. After a median of 8 years, functional outcomes and social attainment were self-reported during adulthood (n = 3114, median age = 22 years, IQR = 20-24 years). Multivariable log-binomial models evaluated associations among risk factors, medication use, and adult outcomes. RESULTS: Higher prevalence of psychoactive medication use was reported in survivors compared with siblings (18.3% vs 6.6%; 2-sided P < .001), with trends for increasing antidepressant and stimulant use in recent treatment eras. After adjusting for cancer treatment and baseline cognitive problems, psychoactive medication use during adolescence was associated with impaired task efficiency (relative risk [RR] = 1.20, 95% confidence interval [CI] = 1.01 to 1.43) and memory (RR = 1.27, 95% CI = 1.05 to 1.52) during adulthood. Survivors who reported continued use of medications from adolescence to adulthood demonstrated poorer emotional regulation (RR = 1.68, 95% CI = 1.24 to 2.27) and organization (RR = 1.82, 95% CI = 1.28 to 2.59) compared with nonusers. Adolescent opioid use was associated with somatization symptoms (RR = 1.72, 95% CI = 1.09 to 2.73) during adulthood, after adjusting for cancer treatment and baseline behavioral problems. They were also more likely to not complete college (RR = 1.21, 95% CI = 1.04 to 1.41) or work full-time (RR = 1.60, 95% CI = 1.23 to 2.08) compared with nonusers. CONCLUSION: Use of psychoactive medication is more prevalent among adolescent survivors compared with siblings and does not normalize adult outcomes, as evidenced by poorer functional outcomes during young adulthood.

Sertraline Pharmacokinetics in HIV-Infected and Uninfected Children, Adolescents, and Young Adults.

Objective: Due to potential disease and drug interactions, the appropriate sertraline starting dose and titration range may require adjustment in pediatric patients living with HIV. This is the first report of sertraline pharmacokinetics in HIV-infected youth. Methods: IMPAACT P1080 was a multicenter pilot study describing psychiatric medication pharmacokinetics in HIV-infected and uninfected youth. Participants were stable on sertraline, >6 to <25 years old, and (1) HIV-uninfected (HIV(-)), (2) HIV-infected taking efavirenz (EFV), or (3) HIV-infected taking boosting ritonavir/protease inhibitor (PI/r). Sampling occurred at pre-dose, 2, 4, 6, 12, and 24-h post-dose. Analyses were performed for sertraline and N-desmethylsertraline, and CYP2D6 phenotyping was completed with dextromethorphan. Results: Thirty-one participants (16 HIV(-), 12 PI/r, and 3 EFV) had median (range) weight, age, and dose of 69.5 (31.5-118.2) kg, 21.8 (9.1-24.7) years, and 75.0 (12.5-150.0) mg once daily. Sertraline exposure was highest for HIV(-) and lowest for EFV cohorts; median dose-normalized AUC 0-24 was 1176 (HIV(-)), 791 (PI/r) and 473 (EFV) ng*hr/mL, and C24 was 32.7 (HIV(-)), 20.1 (PI/r), and 12.8 (EFV) ng/mL. The urinary dextromethorphan/dextrorphan (DXM/DXO) ratio was higher in HIV(-) vs. PI/r cohorts (p = 0.01). Four HIV(-) participants were CYP2D6 poor metabolizers (ln(DXM/DXO) of >-0.5). Conclusions: HIV(-) cohort had the highest sertraline exposure. Sertraline exposure was ~40% lower in the PI/r cohort than in HIV(-); the need to alter sertraline dose ranges for PI/r participants is not clear. The impact of efavirenz on sertraline needs further investigation due to limited numbers of EFV participants.

Propelling the Pediatric HIV Therapeutic Agenda With Science, Innovation, and Collaboration.

BACKGROUND: A number of well-described obstacles to the pediatric therapeutic agenda have resulted in substantial delays in the introduction of new medications, formulations, strategies, and approaches to treat infants, children, and adolescents living with HIV. SETTING: Global landscape. METHODS: The authors will provide a summary of current and emerging initiatives to accelerate the pediatric therapeutic agenda including illustrative case studies of innovations and scientific discovery in diagnosis and treatment of very young children with HIV infection. RESULTS: The challenges posed by rapid physiologic and developmental changes that characterize the trajectory of childhood as well as the complex regulatory and fiscal milieu of HIV therapeutics have hampered pediatric HIV therapeutic research. Recent efforts to accelerate this agenda include prioritizing agents and formulations, defining dosing by weight bands, applying innovative study designs, synergizing work across research networks to achieve common goals, and the establishment of a global prioritized research agenda. A case study of initiatives to diagnose and effectively treat newborns and infants will illustrate the critical role of basic science research and novel approaches to study design and implementation that are informing global efforts to end AIDS. CONCLUSIONS: A pediatric therapeutic agenda informed by basic science and achieved through innovation and global cooperation is essential to achieve an AIDS-free generation.

Long-term psychological and educational outcomes for survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

BACKGROUND: Neuroblastoma survivors may be at elevated risk for psychological impairments because of their young age at diagnosis and neurotoxic treatment, but this is not well described. METHODS: A total of 859 ≥5-year survivors of neuroblastoma younger than 18 years (diagnosed in 1970-1999), who had a median age at diagnosis of 0.8 years (range: 0.0-7.3 years) and a median follow-up of 13.3 years (range: 8.0-17.9 years), were compared with 872 siblings of childhood cancer survivors who were younger than 18 years with the parent-reported Behavior Problem Index (BPI) for psychological functioning. Age- and sex-adjusted multivariate log-binomial models were used to identify factors associated with impairment in BPI domains (scores worse than the sibling 10th percentile). The impact of psychological impairment on educational outcomes was examined among survivors. RESULTS: Compared with siblings, neuroblastoma survivors had an increased prevalence of impairment in the domains of anxiety/depression (19% vs 14%; P = .003), headstrong behavior (19% vs 13%; P < .001), attention deficits (21% vs 13%; P < .001), peer conflict/social withdrawal (26% vs 17%; P < .001), and antisocial behavior (16% vs 12%; P = .01). Common treatment exposures (vincristine, cisplatin, and retinoic acid) were not associated with impairment. Having 2 or more chronic health conditions predicted impairment in 4 domains (P < .001). Specifically, pulmonary disease predicted impairment in all 5 domains (P ≤ .004). Endocrine disease (P ≤ .004) and peripheral neuropathy (P ≤ .02) each predicted impairment in 3 domains. Psychological impairment was associated with special education service usage and educational attainment less than college. CONCLUSIONS: Neuroblastoma survivors are at elevated risk for psychological impairment, which is associated with special education service usage and lower adult educational attainment. Those with chronic health conditions may represent a high-risk group for targeted screening and intervention. Cancer 2018. © 2018 American Cancer Society.

Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial.

Background: Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods: The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results: Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions: Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.

Assessing Psychiatric Symptoms in Youth Affected by HIV: Comparing a Brief Self-Administered Rating Scale with a Structured Diagnostic Interview.

Brief psychiatric assessment tools are needed for evaluating children affected by HIV for emotional and behavioral problems. We compared a self-administered symptom rating scale (CASI-4R) to a semi-structured diagnostic interview (DICA-P) in 136 U.S. children affected by HIV. Agreement and performance measures for the two instruments were computed for attention deficit hyperactivity disorder, depression, anxiety, and disruptive behavior. Correlations and regression analyses were conducted to compare the two instruments, and to evaluate their associations with social, academic, and global function. Higher CASI-4R symptom severity scores were associated with DICA diagnoses (p < 0.02 for all disorders). Agreement (κ) between DICA diagnoses and CASI-4R Clinical Cutoffs (which incorporated symptoms and impairment) was low to moderate (0.19-0.40 for all disorders). Thirty-two percent of cases with a DICA diagnosis were identified by the CASI-4R Clinical Cutoff (sensitivity), yet over 90% of DICA-negative cases were negative by the CASI-4R (specificity). Sensitivity was higher using CASI-4R Severity Score thresholds based on median scores compared to the DICA diagnoses. The presence and severity of psychiatric symptoms and impairment were associated with poorer academic, social, and global function. The CASI-4R symptom checklist can be used to inexpensively screen youth affected by HIV for emotional and behavioral problems, although it is important that there be appropriate mental health evaluation follow-up.

The Behavior Rating Inventory of Executive Function (BRIEF) to Identify Pediatric Acute Lymphoblastic Leukemia (ALL) Survivors At Risk for Neurocognitive Impairment.

Neurocognitive problems, including executive dysfunction, are potential late effects of pediatric acute lymphoblastic leukemia treatment. Surveillance for neurocognitive impairment in a timely and efficient manner is imperative to ongoing clinical care. We sought to determine if the Behavior Rating Inventory of Executive Function (BRIEF) Parent Form identified leukemia survivors with cognitive impairment. In this 28-site cross-sectional study, parents of 256 children, a mean of 8.9±2.2 years after treatment for standard-risk precursor-B acute lymphoblastic leukemia and in first remission, completed the BRIEF. We used a multivariate logistic regression to calculate the association between elevated scores on 3 composite BRIEF indices (Behavioral Regulation Index, Metacognition Index, Global Executive Composite [GEC]) and special education and attention-deficit/hyperactivity disorder (ADHD) outcomes. All BRIEF index scores were significantly associated with receipt of special education services or ADHD. The BRI was most strongly associated with ADHD (odds ratios=4.33; 95% confidence interval, 1.72-10.9). The GEC was most strongly associated with ADHD (odds ratios=4.46; 95% confidence interval, 1.77-11.22). Elevated scores on the BRIEF GEC were associated with low sensitivity (24.1 to 39.1) for detecting the outcomes but better specificity (range, 87.7 to 89.3). These results suggest that the parent-completed BRIEF is associated with clinical outcomes but is not a sensitive tool to identify leukemia survivors that require a comprehensive neuropsychological assessment.

The Association Between Motor Skills and Academic Achievement Among Pediatric Survivors of Acute Lymphoblastic Leukemia.

OBJECTIVE: Assess the association between fine motor (FM) and visual-motor integration (VMI) skills and academic achievement in pediatric acute lymphoblastic leukemia (ALL) survivors. METHODS: In this 28-site cross-sectional study of 256 children in first remission, a mean of 8.9 ± 2.2 years after treatment for standard-risk precursor-B ALL, validated measures of FM, VMI, reading, math, and intelligence were administered at mean follow-up age of 12.8 ± 2.5 years. RESULTS: VMI was significantly associated with written math calculation ability (p < .0069) after adjusting for intelligence (p < .0001). VMI was more strongly associated with math in those with lower intelligence (p = .0141). Word decoding was also significantly associated with VMI but with no effect modification by intelligence. FM skills were not associated with either reading or math achievement. CONCLUSION: These findings suggest that VMI is associated with aspects of math and reading achievement in leukemia survivors. These skills may be amenable to intervention.

Everyday executive function in standard-risk acute lymphoblastic leukemia survivors.

We aimed to evaluate parent-rated executive function (EF) in pediatric standard risk acute lymphoblastic leukemia (SR-ALL) survivors compared to a healthy comparison (HC) group. We hypothesized that SR-ALL survivors would have greater reported executive dysfunction compared to HC, and that those younger at the time of treatment would demonstrate greater EF difficulties. A sample of 256 SR-ALL survivors evaluated an average nine years after treatment were compared to HC matched for gender, assessment age, and maternal education. Profile analysis was used to compare the groups across EF scales on the BRIEF. The prevalence of clinical elevations in the groups was compared via chi square, and odds ratios were calculated. Regression models were applied to examine the role of age at diagnosis and age at assessment in reported EF. Results indicated that SR-ALL survivors' mean scores of EF are similar to HC, except for flexibility and initiation. Survivors were rated as having clinical impairments with flexibility, initiation, working memory, and emotional control at rates two to three times that of HC. The risk of working memory and self-monitoring deficits was greater in survivors who were older when assessed. There was no relationship between age at diagnosis or treatment regimen on EF. These findings suggest sparing of extensive and severe EF deficits in SR-ALL survivors overall. However, a subset of survivors displays clinically significant executive dysfunction. There appears to be a heightened susceptibility to disrupted metacognitive functions as survivors age. This has implications for how we monitor neurocognitive development and functioning of SR-ALL survivors, and highlights opportunities for cognitive interventions.

A multi-disciplinary approach to implementation science: the NIH-PEPFAR PMTCT implementation science alliance.

In resource-limited countries, interventions to prevent mother-to-child HIV transmission (PMTCT) have not yet realized their full potential health impact, illustrating the common gap between the scientific proof of an intervention's efficacy and effectiveness and its successful implementation at scale into routine health services. For PMTCT, this gap results, in part, from inadequate adaptation of PMTCT interventions to the realities of the implementation environment, including client and health care worker behaviors and preferences, health care policies and systems, and infrastructure and resource constraints. Elimination of mother-to-child HIV transmission can only be achieved through understanding of key implementation barriers and successful adaptation of scientifically proven interventions to the local environment. Central to such efforts is implementation science (IS), which aims to investigate and address major bottlenecks that impede effective implementation and to test new approaches to identifying, understanding, and overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions. Advancing IS will require deliberate and strategic efforts to facilitate collaboration, communication, and relationship-building among researchers, implementers, and policy-makers. To speed the translation of effective PMTCT interventions into practice and advance IS more broadly, the US National Institutes of Health, in collaboration with the President's Emergency Plan for AIDS Relief launched the National Institutes of Health/President's Emergency Plan for AIDS Relief PMTCT IS Alliance, comprised of IS researchers, PMTCT program implementers, and policy-makers as an innovative platform for interaction and coordination.

Association between lymphocyte and monocyte subsets and cognition in children with HIV.

BACKGROUND: This study assesses the relationships between lymphocyte and monocyte subsets and intelligence quotient (IQ) scores in antiretroviral therapy (ART)-naive, HIV-infected Thai children without advanced HIV disease. FINDINGS: Sixty-seven ART-naive Thai children with CD4 between 15-24% underwent cognitive testing by Weschler intelligence scale and had 13 cell subsets performed by flow cytometry including naive, memory and activated subsets of CD4+ and CD8+ T cells, activated and perivascular monocytes and B cells. Regression modelling with log10 cell count and cell percentage transformation was performed.Median age (IQR) was 9 (7-10) years, 33% were male, CDC stages N:A:B were 1:67:31%, median CD4% and count (IQR) were 21 (18-24)%, 597 (424-801) cells/mm3 and HIV RNA (IQR) was 4.6 (4.1-4.9) log10 copies/ml. Most (82%) lived at home, 45% had a biological parent as their primary caregiver, and 26 (49%) had low family income. The mean (SD) scores were 75 (13) for full scale IQ (FIQ), 73 (12) for verbal IQ (VIQ) and 80 (14) for performance IQ (PIQ). Adjusted multivariate regression analysis showed significant negative associations between B cell counts and FIQ, VIQ and PIQ (p < 0.01 for all); similar associations were found for B cell percentages (p < 0.05 for all). CONCLUSIONS: High B cell counts and percentages were strongly associated with poorer FIQ, VIQ and PIQ scores. Prospective, long-term assessment of cell subsets and determination of relevant B cell subpopulations could help further elucidate associations between lymphocyte subsets and neurocognitive development.

An analysis of select emerging executive skills in perinatally HIV-1-infected children.

This study examined the effect of perinatal HIV-1 infection on emerging executive skills in children (n = 161) ages 8 to 12 years. HIV-positive (n = 76) and HIV-negative (n = 85) children were eligible to participate. The HIV-positive children included those who had experienced a CDC Class C event (greater severity, n = 22) and those who were HIV-positive but who had not experienced a CDC Class C event (less severity, n = 54). Measures of emerging executive functions completed by the children included subtests from the Developmental Neuropsychological Assessment (NEPSY), the Trail-Making Test-Part B, and a subtest from the Woodcock-Johnson Battery-Revised. Ratings of executive functions were obtained from caretakers using the Behavior Rating Inventory of Executive Functions. Generalized estimating equations methods, discriminate analyses, and global deficit score analyses were performed to determine whether differences emerged between the three clinical groups while using strict controls. The present results revealed significant group differences in unadjusted mean scores measuring executive functioning. However, such differences did not remain statistically significant when moderating variables were taken into consideration in the models. The apparent deficit in executive functioning for the HIV-positive children was found to be largely due to differential psychosocial and environmental factors rather than HIV disease and its severity, and in this cohort, the effects of HIV-1 infection on emerging executive functions appeared to be negligible when controlling for treatment and moderating psychosocial variables.

Assessing psychological well-being: self-report instruments for the NIH Toolbox.

OBJECTIVE: Psychological well-being (PWB) has a significant relationship with physical and mental health. As a part of the NIH Toolbox for the Assessment of Neurological and Behavioral Function, we developed self-report item banks and short forms to assess PWB. STUDY DESIGN AND SETTING: Expert feedback and literature review informed the selection of PWB concepts and the development of item pools for positive affect, life satisfaction, and meaning and purpose. Items were tested with a community-dwelling US Internet panel sample of adults aged 18 and above (N = 552). Classical and item response theory (IRT) approaches were used to evaluate unidimensionality, fit of items to the overall measure, and calibrations of those items, including differential item function (DIF). RESULTS: IRT-calibrated item banks were produced for positive affect (34 items), life satisfaction (16 items), and meaning and purpose (18 items). Their psychometric properties were supported based on the results of factor analysis, fit statistics, and DIF evaluation. All banks measured the concepts precisely (reliability ≥0.90) for more than 98% of participants. CONCLUSION: These adult scales and item banks for PWB provide the flexibility, efficiency, and precision necessary to promote future epidemiological, observational, and intervention research on the relationship of PWB with physical and mental health.

Participation and retention of youth with perinatal HIV infection in mental health research studies: the IMPAACT P1055 psychiatric comorbidity study.

BACKGROUND: Obtaining accurate estimates of mental health problems among youth perinatally infected with HIV (PHIV) helps clinicians develop targeted interventions but requires enrollment and retention of representative youth into research studies. METHODS: The study design for IMPAACT P1055, a US-based, multisite prospective study of psychiatric symptoms among PHIV youth and uninfected controls aged 6 to 17 years old, is described. Participants were compared with nonparticipants by demographic characteristics and reasons were summarized for study refusal. Adjusted logistic regression models were used to evaluate the association of psychiatric symptoms and other factors with loss to follow-up (LTFU). RESULTS: Among 2281 youth screened between 2005 and 2006 at 29 IMPAACT research sites, 580 (25%) refused to participate, primarily because of time constraints. Among 1162 eligible youth approached, 582 (50%) enrolled (323 PHIV and 259 Control), with higher participation rates for Hispanic youth. Retention at 2 years was significantly higher for PHIV than Controls (84% vs 77%, P = 0.03). In logistic regression models adjusting for sociodemographic characteristics and HIV status, youth with any self-assessed psychiatric condition had higher odds of LTFU compared with those with no disorder (adjusted odds ratio = 1.56, 95% confidence interval: 1.00 to 2.43). Among PHIV youth, those with any psychiatric condition had 3-fold higher odds of LTFU (adjusted odds ratio = 3.11, 95% confidence interval: 1.61 to 6.01). CONCLUSIONS: Enrollment and retention of PHIV youth into mental health research studies is challenging for those with psychiatric conditions and may lead to underestimated risks for mental health problems. Creative approaches for engaging HIV-infected youth and their families are required for ensuring representative study populations.

Emotion assessment using the NIH Toolbox.

One of the goals of the NIH Toolbox for Assessment of Neurological and Behavioral Function was to identify or develop brief measures of emotion for use in prospective epidemiologic and clinical research. Emotional health has significant links to physical health and exerts a powerful effect on perceptions of life quality. Based on an extensive literature review and expert input, the Emotion team identified 4 central subdomains: Negative Affect, Psychological Well-Being, Stress and Self-Efficacy, and Social Relationships. A subsequent psychometric review identified several existing self-report and proxy measures of these subdomains with measurement characteristics that met the NIH Toolbox criteria. In cases where adequate measures did not exist, robust item banks were developed to assess concepts of interest. A population-weighted sample was recruited by an online survey panel to provide initial item calibration and measure validation data. Participants aged 8 to 85 years completed self-report measures whereas parents/guardians responded for children aged 3 to 12 years. Data were analyzed using a combination of classic test theory and item response theory methods, yielding efficient measures of emotional health concepts. An overview of the development of the NIH Toolbox Emotion battery is presented along with preliminary results. Norming activities led to further refinement of the battery, thus enhancing the robustness of emotional health measurement for researchers using the NIH Toolbox.

Norming plans for the NIH Toolbox.

OBJECTIVE: The NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox) is a comprehensive battery of brief assessment tools. The purpose of this article is to describe plans to establish normative reference values for the NIH Toolbox measures. METHODS: A large sample will be obtained from the US population for the purpose of calculating normative values. The sample will be stratified by age (ages 3-85 years), sex, and language preference (English or Spanish) and have a total sample size of at least 4,205. The sample will include a minimum of 25-100 individuals in each targeted demographic and language subgroup. RESULTS: Norming methods will include poststratification adjustment calculated using iterative proportional fitting, also known as raking, so that the weighted sample will have the same distribution on key demographic variables as the US population described in the 2010 Census. CONCLUSIONS: As with any set of norms, users should be mindful of the reference population and make conclusions consistent with the limitations of normative sampling, since it is not a probability-based sample. However, the NIH Toolbox norming study has been designed to minimize bias and maximize representativeness and precision of estimates. The availability of a "toolbox" of normed measures will be an important foundation for addressing critical research questions in neurologic and behavioral health.