ABSTRACT
Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.
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BACKGROUND: Integrating behavioral health services into pediatric primary care can improve access to care, especially for children marginalized by poverty and racial/ethnic minority status. In primary care, a common presenting concern is attention-deficit/hyperactivity disorder (ADHD). Services in primary care for marginalized children with ADHD typically include medication alone; therapy to improve skills and build relationships is less available. This study evaluates the effectiveness of a behavioral intervention offered through primary care for marginalized families coping with ADHD (Partnering to Achieve School Success, PASS) compared to treatment as usual (TAU). METHOD: Three hundred participants will be randomly assigned to PASS or TAU. Participants include children ages 5 to 11 who have ADHD and are from economically marginalized families. PASS is a personalized, enhanced behavioral intervention that includes evidence-based behavior therapy strategies and enhancements to promote family engagement, increase caregiver distress tolerance, and provide team-based care to improve academic and behavioral functioning. TAU includes services offered by primary care providers and referral for integrated behavioral health or community mental health services. Outcomes will be assessed at mid-treatment (8 weeks after baseline), post-treatment (16 weeks), and follow-up (32 weeks) using parent- and teacher-report measures of service use, child academic, behavioral, and social functioning, parenting practices, family empowerment, and team-based care. Mixed effects models will examine between-group differences at post-treatment and follow-up. Analyses will examine the mediating role of parenting practices, family empowerment, and team-based care. Subgroup analyses will examine differential effects of intervention by child clinical characteristics and socioeconomic factors. DISCUSSION: This study is unique in targeting a population of children with ADHD marginalized by low socioeconomic resources and examining an intervention designed to address the challenges of families coping with chronic stress related to poverty. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov (NCT04082234) on September 5, 2019, prior to enrollment of the first participant. The current version of the protocol and IRB approval date is October 4, 2023. Results will be submitted to ClinicalTrials.gov no later than 30 days prior to the due date for the submission of the draft of the final research report to the Patient-Centered Outcomes Research Institute.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Behavior Therapy , Primary Health Care , Humans , Attention Deficit Disorder with Hyperactivity/therapy , Child , Child, Preschool , Behavior Therapy/methods , Healthcare Disparities , Male , Female , PovertyABSTRACT
Purpose: The COVID-19 pandemic posed challenges to measuring mother-infant interactions, a critical outcome for many interventions to support mothers with postpartum depression symptoms and their new infants. The current study describes the process and lessons learned from implementing a remote assessment of mother-infant interactions during the pandemic. Description: At the onset of the COVID-19 pandemic, we pivoted from in-person to using two different strategies to remotely assess mother-infant interactions: (1) participants independently recorded and uploaded videos of free-play with their child; and (2) research team conducted a live-video recording of the free-play. Assessment: We found initial barriers including technical and video quality issues but overall, a remote option could increase enrollment and retention rates in a sample of postpartum women across various racial/ethnic groups and economic levels. Conclusion: Our experiences in conducting remote assessments with postpartum women add to growing evidence for the feasibility and validity of remote visits. This showed how our methods can be implemented in future research and in practice with postpartum mothers and their infants.
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OBJECTIVE: To determine feasibility, acceptability, and explore outcomes of behavioral economic (BE) strategies to increase parent-child shared reading within a Reach Out and Read program. METHODS: We conducted rapid-cycle interviews with 10 parents to assess text messages followed by an 8-week randomized controlled trial of 3 BE strategies at 2 urban primary care practices: daily text messages (texting); daily text messages and regret messaging (regret); or daily text messages, regret messaging, and lottery participation (lottery). Parent-child dyads were eligible if children were <24 months old, Medicaid-eligible, and had access to phones capable of receiving and sending text messages. Parents completed the Read Subscale of the StimQ and Parenting Stress Index-short form (PSI-SF) pre- and postintervention, MacArthur Communicative Development Inventory (CDI), Devereux Early Childhood Assessment (DECA), and a satisfaction measure postintervention. Differences between groups were assessed using intention-to-treat analysis. RESULTS: Of 45 dyads randomized, 41 (91%) completed the study. Most participants were Black with incomes <$55,000. Parents reported reading on average 4 d/wk with no change in the reading frequency over time. StimQ scores increased over time, but there were no significant differences in StimQ, PSI-SF, CDI, and DECA scores between groups. Parents in all 3 groups reported satisfaction (3.8/5.0) with the intervention. CONCLUSIONS: Implementation of BE strategies in 2 Reach Out and Read programs was feasible, near acceptable, and improved home reading environment scores. Future study should investigate BE strategies vis-à-vis usual care and be of sufficient duration and intensity to engage participants to assess its impact on patient and parent outcomes.
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Background Poor interstage weight gain is a risk factor for adverse outcomes in infants with hypoplastic left heart syndrome. We sought to examine the association of neighborhood social vulnerability and interstage weight gain and determine if this association is modified by enrollment in our institution's Infant Single Ventricle Management and Monitoring Program (ISVMP). Methods and Results We performed a retrospective single-center study of infants with hypoplastic left heart syndrome before (2007-2010) and after (2011-2020) introduction of the ISVMP. The primary outcome was interstage weight gain, and the secondary outcome was interstage growth failure. Multivariable linear and logistic regression models were used to examine the association between the Social Vulnerability Index and the outcomes. We introduced an interaction term into the models to test for effect modification by the ISVMP. We evaluated 217 ISVMP infants and 111 pre-ISVMP historical controls. The Social Vulnerability Index was associated with interstage growth failure (P=0.001); however, enrollment in the ISVMP strongly attenuated this association (P=0.04). Pre-ISVMP, as well as high- and middle-vulnerability infants gained 4 g/d less and were significantly more likely to experience growth failure than low-vulnerability infants (high versus low: adjusted odds ratio [aOR], 12.5 [95% CI, 2.5-62.2]; middle versus low: aOR, 7.8 [95% CI, 2.0-31.2]). After the introduction of the ISVMP, outcomes did not differ by Social Vulnerability Index tertile. Infants with middle and high Social Vulnerability Index scores who were enrolled in the ISVMP gained 4 g/d and 2 g/d more, respectively, than pre-ISVMP controls. Conclusions In infants with hypoplastic left heart syndrome, high social vulnerability is a risk factor for poor interstage weight gain. However, enrollment in the ISVMP significantly reduces growth disparities.
Subject(s)
Hypoplastic Left Heart Syndrome , Univentricular Heart , Infant , Humans , Hypoplastic Left Heart Syndrome/diagnosis , Hypoplastic Left Heart Syndrome/surgery , Retrospective Studies , Social Vulnerability , Logistic Models , Weight GainABSTRACT
The purpose of this scoping review is to determine trends in racial and ethnic representation, identify barriers and facilitators to greater diversity, and assess strategies and interventions to advance diversity among those in the pediatric research workforce in the U.S. We conducted a scoping review of PubMed supplemented with the authors' personal library of papers published from January 1, 2010, to December 31, 2021. To be eligible, papers had to provide original data, be published in English, report information from a U.S. healthcare institution, and report on outcomes of interest relevant to the child health field. The diversity of faculty has modestly increased over the past decade but reflects a worsening representation compared to overall population trends. This slow increase reflects a loss of diverse faculty and has been referred to as a "leaky pipeline." Strategies to plug the "leaky pipeline" include greater investments in pipeline programs, implementation of holistic review and implicit bias training, development of mentoring and faculty programs targeted to diverse faculty and trainees, alleviation of burdensome administrative tasks, and creation of more inclusive institutional environments. Modest improvements in the racial and ethnic diversity of the pediatric research workforce were identified. However, this reflects worsening overall representation given changing U.S. population demographics. IMPACT: Racial and ethnic diversity in the pediatric research workforce has shown modest increases but worsening overall representation. This review identified barriers and facilitators at the intrapersonal, interpersonal, and institutional levels that impact BIPOC trainees and faculty career advancement. Strategies to improve the pathway for BIPOC individuals include greater investments in pipeline and educational programs, implementation of holistic review admissions and bias training, institution of mentoring and sponsorship, alleviation of burdensome administrative responsibilities, and creation of inclusive institutional climates. Future studies should rigorously test the effects of interventions and strategies designed to improve diversity in the pediatric research workforce.
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Mentoring , Child , Humans , Mentors , Research , Workforce , Cultural DiversityABSTRACT
OBJECTIVES: To test effects of a social media-based parenting program for mothers with postpartum depressive symptoms. METHODS: We conducted a randomized controlled trial from December 2019 to August 2021 of a parenting program using Facebook. Women with mild-to-moderate depressive symptoms (Edinburgh Postnatal Depression Scale [EPDS] 10-19) were randomized to the program, plus online depression treatment or depression treatment alone for 3 months. Women completed the EPDS monthly and the Parent-Child Early Relational Assessment, Parenting Stress Index-Short Form, and Parenting Sense of Competence pre- and postintervention. Differences among groups were assessed using intention-to-treat analysis. RESULTS: Seventy-five women enrolled and 66 (88%) completed the study. Participants were predominantly Black (69%), single (57%), with incomes <$55 000 (68%). The parenting group reported a more rapid decline in depressive symptoms than the comparison group (adjusted EPDS difference, -2.9; 95% confidence interval, -4.8 to -1.0 at 1 month). There were no significant group X time interactions for the Parent-Child Early Relational Assessment, Parenting Stress Index-Short Form, or Parenting Sense of Competence scores. Forty-one percent of women sought mental health treatment for worsening symptoms or suicidality. Women in the parenting group who exhibited greater engagement or reported mental health treatment had greater parenting responsiveness. CONCLUSIONS: A social media-based parenting program led to more rapid declines in depressive symptoms but no differences in responsive parenting, parenting stress, or parenting competence relative to a comparison group. Social media can provide parenting support for women with postpartum depressive symptoms, but greater attention to engagement and treatment access are needed to improve parenting outcomes.
Subject(s)
Depression, Postpartum , Social Media , Female , Humans , Depression/therapy , Depression, Postpartum/diagnosis , Depression, Postpartum/therapy , Parenting/psychology , Postpartum Period , Mothers/psychologyABSTRACT
Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are among the most common rare genetic disorders associated with significant risk for neuropsychiatric disorders across the lifespan. Microdeletions and duplications in these loci are associated with neurocognitive deficits, yet there are few studies comparing these groups using the same measures. We address this gap in a prospective international collaboration applying the same computerized neurocognitive assessment. The Penn Computerized Neurocognitive Battery (CNB) was administered in a multi-site study on rare genomic disorders: 22q11.2 deletion (n = 397); 22q11.2 duplication (n = 77); 16p11.2 deletion (n = 94); and 16p11.2 duplication (n = 26). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and sensori-motor speed. Accuracy and speed for each neurocognitive domain were included as dependent measures in a mixed-model repeated measures analysis, with locus (22q11.2, 16p11.2) and copy number (deletion/duplication) as grouping factors and neurocognitive domain as a repeated measures factor, with age and sex as covariates. We also examined correlation with IQ and site effects. We found that 22q11.2 deletions were associated with greater deficits in overall performance accuracy than 22q11.2 duplications, while 16p11.2 duplications were associated with greater deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed. Performance profiles differed among the groups with particularly poor performance of 16p11.2 duplication on non-verbal reasoning and social cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. No site effects were observed. Deletions and duplications of 22q11.2 and 16p11.2 have varied effects on neurocognition indicating locus specificity, with performance profiles differing among the groups. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome. Future studies could aim to link performance profiles to clinical features and brain function.
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Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 309 cases and 299 controls, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10-4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function-related gene, in Japanese ASD. The overall results of this case-control exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.
Subject(s)
Autism Spectrum Disorder , Exome , Autism Spectrum Disorder/genetics , Case-Control Studies , Exome/genetics , Genetic Predisposition to Disease , Humans , JapanABSTRACT
The genetic etiology of autism spectrum disorder (ASD) is multifactorial, but how combinations of genetic factors determine risk is unclear. In a large family sample, we show that genetic loads of rare and polygenic risk are inversely correlated in cases and greater in females than in males, consistent with a liability threshold that differs by sex. De novo mutations (DNMs), rare inherited variants and polygenic scores were associated with various dimensions of symptom severity in children and parents. Parental age effects on risk for ASD in offspring were attributable to a combination of genetic mechanisms, including DNMs that accumulate in the paternal germline and inherited risk that influences behavior in parents. Genes implicated by rare variants were enriched in excitatory and inhibitory neurons compared with genes implicated by common variants. Our results suggest that a phenotypic spectrum of ASD is attributable to a spectrum of genetic factors that impact different neurodevelopmental processes.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Autism Spectrum Disorder/genetics , Autistic Disorder/genetics , Child , Family , Female , Genetic Predisposition to Disease , Humans , Male , Multifactorial Inheritance/geneticsABSTRACT
BACKGROUND: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL. PROCEDURE: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors. RESULTS: We identified 126 eligible patients, of whom 63% were documented as White, non-Hispanic, 28% as non-White, non-Hispanic, and 9% as Hispanic. Twenty-eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78-0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47-8.36). CONCLUSIONS: Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children.
Subject(s)
Chemical and Drug Induced Liver Injury , Hypoglycemia , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Child , Child, Preschool , Humans , Hypoglycemia/chemically induced , Hypoglycemia/epidemiology , Incidence , Infant , Maintenance Chemotherapy/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Retrospective Studies , Risk FactorsABSTRACT
OBJECTIVE: To evaluate the impact of a Cleft Nurse Navigator (CNN) program on care for patients with cleft lip and cleft palate and assess the programs efficacy to reduce existing socioeconomic disparities in care. DESIGN: Retrospective review and outcomes analysis (n = 739). SETTING: Academic tertiary care center. PATIENTS: All patients presenting with cleft lip and/or cleft palate (CL/P) born between May 2009 and November 2019 with exclusions for atypical clefts, submucous cleft palates, international adoption, and very late presentation (after 250 days of life). INTERVENTIONS: Multidisciplinary care coordination program facilitated by the CNN. MAIN OUTCOME MEASURES: Patient age at first outpatient appointment and age at surgery, reported feeding issues, weight gain, and patient-cleft team communications. RESULTS: After CNN implementation, median age at outpatient appointment decreased from 20 to 16 days (P = .021), volume of patient-cleft team communications increased from 1.5 to 2.8 (P < .001), and frequency of reported feeding concerns decreased (50% to 35%; P < .001). In the pre-CNN cohort, nonwhite and publicly insured patients experienced delays in first outpatient appointment (P < .001), cleft lip repair (P < .011), and cleft palate repair (P < .019) compared to white and privately insured patients, respectively. In the post-CNN cohort, there were no significant differences in first appointment timing by race nor surgical timing on the basis of racial identity nor insurance type. CONCLUSIONS: A variety of factors lead to delays in cleft care for marginalized patient populations. These findings suggest that a CNN can reduce disparities of access and communication and improve early feeding in at-risk cohorts.
Subject(s)
Cleft Lip , Cleft Palate , Cleft Lip/surgery , Cleft Palate/surgery , Humans , Retrospective Studies , Socioeconomic Factors , Weight GainABSTRACT
OBJECTIVES: To compare the effectiveness of care management combined with a patient portal versus a portal alone for communication among children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Randomized controlled trial conducted at 11 primary care practices. Children aged 5 to 12 years old with ADHD were randomly assigned to care management + portal or portal alone. The portal included parent-reported treatment preferences and goals, medication side effects, and parent- and teacher-reported ADHD symptom scales. Care managers provided education to families; communicated quarterly with parents, teachers, and clinicians; and coordinated care. The main outcome, changes in the Vanderbilt Parent Rating Scale (VPRS) score as a measure of ADHD symptoms, was assessed using intention-to-treat analysis. RESULTS: A total of 303 eligible children (69% male; 46% Black) were randomly assigned, and 273 (90%) completed the study. During the 9-month study, parents in the care management + portal arm communicated inconsistently with care managers (mean 2.2; range 0-6) but similarly used the portal (mean 2.3 vs 2.2) as parents in the portal alone arm. In multivariate models, VPRS scores decreased over time (Adjusted ß = -.015; 95% confidence interval -0.023 to -0.07) in both groups, but there were no intervention-by-time effects (Adjusted ß = .000; 95% confidence interval -0.011 to 0.012) between groups. Children who received ≥2 care management sessions had greater reductions in VPRS scores than those with fewer sessions. CONCLUSIONS: Results did not provide evidence that care management combined with a patient portal was different from portal use alone among children with ADHD. Both groups demonstrated similar reductions in ADHD symptoms. Those families with greater care management engagement demonstrated greater reductions than those with less engagement.
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Attention Deficit Disorder with Hyperactivity/therapy , Patient Portals , Child , Child, Preschool , Female , Humans , Male , Prospective Studies , Quality ImprovementABSTRACT
OBJECTIVE: To determine feasibility and explore effects of literacy promotion using e-books versus board books on the home reading environment, book reading, television use, and child development. METHODS: Randomized controlled trial comparing digital literacy promotion (DLP) using e-books to standard literacy promotion (SLP) using board books among Medicaid-eligible infants. DLP participants received e-books on home digital devices, while SLP participants received board books at well visits between 6 and 12 months of age. Differences in StimQ Read Subscale (StimQ-Read) scores, parent-reported reading and television use, and Bayley Scales of Infant Development-3rd Edition (Bayley-3) scores between groups were assessed using intention-to-treat analysis. RESULTS: A total of 104 Medicaid-eligible infants were enrolled and randomized from 3 pediatric practices. There were no differences in sociodemographic characteristics between groups at baseline. Children in the DLP group initially had lower StimQ-Read scores but showed similar increases in StimQ-Read scores over time as children in the SLP group. Parents in the DLP group reported greater use of digital devices to read or engage their child (65% vs 23%, P < .001) but similar board book reading and television viewing. There were no differences between groups in cognitive or motor scale scores, but DLP participants had marginally lower language scales scores (DLP 85.7 vs SLP 89.7; P = .10) at the 6-month follow-up. CONCLUSIONS/DISCUSSION: Literacy promotion using e-books was feasible and associated with greater e-book usage but no difference in board book reading, television viewing, or home reading environment scores. A potential adverse impact of e-books on language development should be confirmed in future study.
Subject(s)
Books , Literacy , Humans , Infant , Language Development , Pilot Projects , Reading , United StatesABSTRACT
Background: Postpartum depression (PPD) is one of the most common birthing complications, and studies negatively associate PPD with breastfeeding initiation and continuation. However, little is known about either the breastfeeding experience of mothers with PPD or what resources mothers need for sustained breastfeeding from their perspectives. This study aimed to identify the antecedents, barriers, and facilitators to breastfeeding for mothers with PPD, understand the relationship between self-efficacy and emergent themes, and generate suggestions to inform supportive interventions. Materials and Methods: Birth mothers who screened positive for PPD and reported breastfeeding were recruited to participate in semistructured interviews. Interviews were transcribed verbatim, and inter-coder discrepancies from double coding were resolved through consensus. Thematic analysis was facilitated using immersion-crystallization methods. Results: Participants identified five antecedent themes that encourage initiation (professional support, infant health, mother's health, cost-effectiveness, and faith), four facilitator themes for sustained breastfeeding (infant connection, decreased stress, personal attributes, and logistical strategies), and seven barrier themes (physical pain, infant nutrition, negative feelings, latching difficulties, medical conditions, public breastfeeding, and sleep). Participants' suggestions fell into three primary themes: supportive services, managing expectations, and respecting self-determination. Conclusion: Antecedent and facilitator themes did not overlap, indicating that factors encouraging breastfeeding initiation differ from sustaining factors. Participant suggestions, barriers, and facilitators did not largely differ from mothers without PPD in other qualitative studies. Therefore, interventions should tailor support to specific breastfeeding phase and may not need to be markedly different for mothers with PPD, in addition to depression management.
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Depression, Postpartum , Mothers , Breast Feeding , Female , Humans , Infant , Qualitative ResearchABSTRACT
MOTIVATION: As sequencing technologies and analysis pipelines evolve, de novo mutation (DNM) calling tools must be adapted. Therefore, a flexible approach is needed that can accurately identify DNMs from genome or exome sequences from a variety of datasets and variant calling pipelines. RESULTS: Here, we describe SynthDNM, a random-forest based classifier that can be readily adapted to new sequencing or variant-calling pipelines by applying a flexible approach to constructing simulated training examples from real data. The optimized SynthDNM classifiers predict de novo SNPs and indels with robust accuracy across multiple methods of variant calling. AVAILABILITYAND IMPLEMENTATION: SynthDNM is freely available on Github (https://github.com/james-guevara/synthdnm). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Importance: Early identification of autism spectrum disorder (ASD) is associated with improved cognitive and behavioral outcomes. Targeted strategies are needed to support equitable access to diagnostic services to ensure that children from low-income and racial/ethnic minority families receive the benefits of early ASD identification and treatment. Objective: To test the efficacy of family navigation (FN), an individually tailored, culturally informed care management strategy, to increase the likelihood of achieving diagnostic ascertainment among young children at risk for ASD. Design, Setting, and Participants: This randomized clinical trial of 249 families of children aged 15 to 27 months who had positive screening results for possible ASD was conducted in 11 urban primary care sites in 3 cities. Data collection occurred from February 24, 2015, through November 5, 2018. Statistical analysis was performed on an intent-to-treat basis from November 5, 2018, to July 27, 2020. Interventions: Families were randomized to FN or conventional care management (CCM). Families receiving FN were assigned a navigator who conducted community-based outreach to families to address structural barriers to care and support engagement in recommended services. Families receiving CCM were assigned to a care manager, who did limited telephone outreach. Families received FN or CCM after positive initial screening results and for 100 days after diagnostic ascertainment. Main Outcomes and Measures: The primary outcome, diagnostic ascertainment, was measured as the number of days from randomization to completion of the child's clinical developmental evaluation, when a diagnosis of ASD or other developmental disorder was determined. Results: Among 250 families randomized, 249 were included in the primary analysis (174 boys [69.9%]; mean [SD] age, 22.0 [3.5] months; 205 [82.3%] publicly insured; 233 [93.6%] non-White). Children who received FN had a greater likelihood of reaching diagnostic ascertainment over the course of 1 year (FN, 108 of 126 [85.7%]; CCM, 94 of 123 [76.4%]; unadjusted hazard ratio [HR], 1.39 [95% CI, 1.05-1.84]). Site (Boston, New Haven, and Philadelphia) and ethnicity (Hispanic vs non-Hispanic) moderated the effect of FN (treatment × site interaction; P = .03; Boston: HR, 2.07 [95% CI, 1.31-3.26]; New Haven: HR, 1.91 [95% CI, 0.94-3.89]; and Philadelphia: HR, 0.91 [95% CI, 0.60-1.37]) (treatment × ethnicity interaction; P < .001; Hispanic families: HR, 2.81 [95% CI, 2.23-3.54] vs non-Hispanic families: HR, 1.49 [95% CI, 1.45-1.53]). The magnitude of FN's effect was significantly greater among Hispanic families than among non-Hispanic families (diagnostic ascertainment among Hispanic families: FN, 90.9% [30 of 33], and CCM, 53.3% [16 of 30]; vs non-Hispanic families: FN, 89.7% [35 of 39], and CCM, 77.5% [31 of 40]). Conclusions and Relevance: Family navigation improved the likelihood of diagnostic ascertainment among children from racial/ethnic minority, low-income families who were detected as at risk for ASD in primary care. Results suggest differential effects of FN by site and ethnicity. Trial Registration: ClinicalTrials.gov Identifier: NCT02359084.