Deborah A. Bilder

Prior epidemiological studies investigating the association between delivery mode (i.e., vaginal birth and cesarean section [C‐section]) and autism spectrum disorder (ASD) and intellectual disability (ID) risk have reported mixed findings. This study examined ASD and ID risks associated with primary and repeat C‐section within diverse US regions. During even years 2000–2016, 8‐years‐olds were identified with ASD and/or ID and matched to birth records [ASD only (N = 8566, 83.6% male), ASD + ID (N = 3445, 79.5% male), ID only (N = 6158, 60.8% male)] using the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network methodology. The comparison birth cohort (N = 1,456,914, 51.1% male) comprised all births recorded in the National Center for Health Statistics corresponding to birth years and counties in which surveillance occurred. C‐section rates in the birth cohort demonstrated significant regional variation with lowest rates in the West. Overall models demonstrate increased odds of disability associated with primary and repeat C‐section. Adjusted models, stratified by region, identified significant variability in disability likelihood associated with repeat C‐section: increased odds occurred for all case groups in the Southeast, for ASD only and ID only in the Mid‐Atlantic, and no case groups in the West. Regional variability in disability risk associated with repeat C‐section coincides with differences in birth cohorts' C‐section rates. This suggests increased likelihood of disability is not incurred by the procedure itself, but rather C‐section serves as a proxy for exposures with regional variability that influence fetal development and C‐section rates.

Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients commonly exhibit intellectual and developmental disabilities, often accompanied by behavior problems, delayed speech, seizures, and motor impairments. There is currently no efficacious treatment for CTD, while the current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements. Efforts to develop effective, sustainable treatments for these disorders are limited by the lack of clinical and patient-derived meaningful outcomes. A core outcome set (COS) can facilitate consensus about outcomes for inclusion in studies. Unfortunately, patient and caregiver perspectives have historically been overlooked in the COS development process, thus limiting their input into the outcome selection. We partnered with caregivers and health professionals to establish the first COS for CTD and GAMT. The COS developed includes seven outcomes (“Adaptive Functioning”, “Cognitive Functioning”, “Emotional Dysregulation”, “MRS Brain Creatine”, “Seizure/Convulsions”, “Expressive Communication”, and “Fine Motor Functions”) for both CTD and GAMT, and an additional outcome for GAMT (“Serum/Plasma Guanidinoacetate”) that are important to stakeholders and consequently should be considered for measurement in every clinical trial. Caregivers were valued partners throughout the COS development process, which increased community engagement and facilitated caregiver empowerment. We expect this COS will ensure a patient-centered approach for accelerating drug development for CTD and GAMT, make clinical trial results comparable, minimize bias in clinical trial outcome selection, and promote efficient use of resources. 1-sentence take home message A core outcome set for creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies was created through a multiphase process in partnership with caregivers and health professionals.

Evidence suggests core autism trait consistency in older children, but development of these traits is variable in early childhood. The Social Responsiveness Scale (SRS) measures autism‐related traits and broader autism phenotype, with two age‐dependent forms in childhood (preschool, 2.5–4.5 years; school age, 4–18 years). Score consistency has been observed within forms, though reliability across forms has not been evaluated. Using data from the Environmental Influences on Child Health Outcomes (ECHO) program (n = 853), preschool, and school‐age SRS scores were collected via maternal report when children were an average of 3.0 and 5.8 years, respectively. We compared reproducibility of SRS total scores (T‐scores) and agreement above a clinically meaningful cutoff (T‐scores ≥ 60) and examined predictors of discordance in cutoff scores across forms. Participant scores across forms were similar (mean difference: 3.3 points; standard deviation: 7), though preschool scores were on average lower than school‐age scores. Most children (88%) were classified below the cutoff on both forms, and overall concordance was high (92%). However, discordance was higher in cohorts following younger siblings of autistic children (16%). Proportions of children with an autism diagnoses were also higher among those with discordant scores (27%) than among those with concordant scores (4%). Our findings indicate SRS scores are broadly reproducible across preschool and school‐age forms, particularly for capturing broader, nonclinical traits, but also suggest that greater variability of autism‐related traits in preschool‐age children may reduce reliability with later school‐age scores for those in the clinical range.

Background: Individuals with developmental disabilities (DD) experience increased rates of emotional and behavioral crises that necessitate assessment and intervention. Psychiatric disorders can contribute to crises; however, screening measures developed for the general population are inadequate for those with DD. Medical conditions can exacerbate crises and merit evaluation. Screening tools using checklist formats, even when designed for DD, are too limited in depth and scope for crisis assessments. The Sources of Distress survey implements a web-based branching logic format to screen for common psychiatric and medical conditions experienced by individuals with DD by querying caregiver knowledge and observations. Objective: This paper aims to (1) describe the initial survey development, (2) report on focus group and expert review processes and findings, and (3) present results from the survey’s clinical implementation and evaluation of validity. Methods: Sources of Distress was reviewed by focus groups and clinical experts; this feedback informed survey revisions. The survey was subsequently implemented in clinical settings to augment providers’ psychiatric and medical history taking. Informal and formal consults followed the completion of Sources of Distress for a subset of individuals. A records review was performed to identify working diagnoses established during these consults. Results: Focus group members (n=17) expressed positive feedback overall about the survey’s content and provided specific recommendations to add categories and items. The survey was completed for 231 individuals with DD in the clinical setting (n=161, 69.7% men and boys; mean age 17.7, SD 10.3; range 2-65 years). Consults were performed for 149 individuals (n=102, 68.5% men and boys; mean age 18.9, SD 10.9 years), generating working diagnoses to compare survey screening results. Sources of Distress accuracy rates were 91% (95% CI 85%-95%) for posttraumatic stress disorder, 87% (95% CI 81%-92%) for anxiety, 87% (95% CI 81%-92%) for episodic expansive mood and bipolar disorder, 82% (95% CI 75%-87%) for psychotic disorder, 79% (95% CI 71%-85%) for unipolar depression, and 76% (95% CI 69%-82%) for attention-deficit/hyperactivity disorder. While no specific survey items or screening algorithm existed for unspecified mood disorder and disruptive mood dysregulation disorder, these conditions were caregiver-reported and working diagnoses for 11.7% (27/231) and 16.8% (25/149) of individuals, respectively. Conclusions: Caregivers described Sources of Distress as an acceptable tool for sharing their knowledge and insights about individuals with DD who present in crisis. As a screening tool, this survey demonstrates good accuracy. However, better differentiation among mood disorders is needed, including the addition of items and screening algorithm for unspecified mood disorder and disruptive mood dysregulation disorder. Additional validation efforts are necessary to include a more geographically diverse population and reevaluate mood disorder differentiation. Future study is merited to investigate the survey’s impact on the psychiatric and medical management of distress in individuals with DD.

Many adults with phenylketonuria (PKU) rely on medical nutrition therapy (MNT; low phenylalanine (Phe) diet with protein substitutes/medical foods) to maintain blood Phe concentrations within recommended ranges and prevent PKU-associated comorbidities. Despite disease detection through newborn screening and introduction of MNT as early as birth, adherence to MNT often deteriorates from childhood onwards, complicating the assessment of its effectiveness in the long term. Via a modified Delphi process, consensus (≥70% agreement) was sought on 19 statements among an international, multidisciplinary 13-member expert panel. After three iterative voting rounds, the panel achieved consensus on 17 statements related to the limitations of the long-term effectiveness of MNT (7), the burden of long-term reliance on MNT (4), and its potential long-term detrimental health effects (6). According to the expert panel, the effectiveness of MNT is limited in the long term, is associated with a high treatment burden, and demonstrates that adults with PKU are often unable to achieve metabolic control through dietary management alone, creating an unmet need in the adult PKU population.

Background: Prenatal exposure to maternal metabolic conditions associated with inflammation and steroid dysregulation has previously been linked to increased autism risk. Steroid-related maternal serum biomarkers have also provided insight into the in utero steroid environment for offspring who develop autism. Objective: This study examines the link between autism among offspring and early second trimester maternal steroid-related serum biomarkers from pregnancies enriched for prenatal metabolic syndrome (PNMS) exposure. Study design: Early second trimester maternal steroid-related serum biomarkers (i.e., estradiol, free testosterone, total testosterone, and sex hormone binding globulin) were compared between pregnancies corresponding to offspring with (N = 68) and without (N = 68) autism. Multiple logistic regression analyses were stratified by sex and gestational duration. One-way ANCOVA with post hoc tests was performed for groups defined by autism status and PNMS exposure. Results: Increased estradiol was significantly associated with autism only in males (AOR = 1.13 per 100 pg/ml, 95% CI 1.01–1.27, p = 0.036) and only term pregnancies (AOR = 1.17 per 100 pg/ml, 95% CI 1.04–1.32, p = 0.010). Autism status was significantly associated with decreased sex hormone binding globulin (AOR = 0.65 per 50 nmol/L, 95% CI 0.55–0.78, p < 0.001) overall and when stratified by sex and term pregnancy status. The inverse association between sex hormone binding globulin and autism was independent of PNMS exposure. Limitations: The relative racial and ethnic homogeneity of Utah’s population limits the generalizability of study results. Although significant differences by autism status were identified in concentrations of sex hormone binding globulin overall and of estradiol in participant subgroups, differences by PNMS exposure failed to reach statistical significance, which may reflect insufficient statistical power. Conclusion: Both elevated maternal serum estradiol in males only and low maternal serum sex hormone binding globulin in both sexes are associated with increased autism risk. Further investigation is merited to identify how steroid, metabolic, and inflammatory processes can interact to influence neurodevelopment in early second trimester.

BACKGROUND Individuals with developmental disabilities (DD) experience increased rates of emotional and behavioral crises that necessitate assessment and intervention. Psychiatric disorders can contribute to crises; however, screening measures developed for the general population are inadequate for those with DD. Medical conditions can exacerbate crises and merit evaluation. Screening tools using checklist formats, even when designed for DD, are too limited in depth and scope for crisis assessments. The Sources of Distress survey implements a web-based branching logic format to screen for common psychiatric and medical conditions experienced by individuals with DD by querying caregiver knowledge and observations. OBJECTIVE This paper aims to (1) describe the initial survey development, (2) report on focus group and expert review processes and findings, and (3) present results from the survey’s clinical implementation and evaluation of validity. METHODS Sources of Distress was reviewed by focus groups and clinical experts; this feedback informed survey revisions. The survey was subsequently implemented in clinical settings to augment providers’ psychiatric and medical history taking. Informal and formal consults followed the completion of Sources of Distress for a subset of individuals. A records review was performed to identify working diagnoses established during these consults. RESULTS Focus group members (n=17) expressed positive feedback overall about the survey’s content and provided specific recommendations to add categories and items. The survey was completed for 231 individuals with DD in the clinical setting (n=161, 69.7% men and boys; mean age 17.7, SD 10.3; range 2-65 years). Consults were performed for 149 individuals (n=102, 68.5% men and boys; mean age 18.9, SD 10.9 years), generating working diagnoses to compare survey screening results. Sources of Distress accuracy rates were 91% (95% CI 85%-95%) for posttraumatic stress disorder, 87% (95% CI 81%-92%) for anxiety, 87% (95% CI 81%-92%) for episodic expansive mood and bipolar disorder, 82% (95% CI 75%-87%) for psychotic disorder, 79% (95% CI 71%-85%) for unipolar depression, and 76% (95% CI 69%-82%) for attention-deficit/hyperactivity disorder. While no specific survey items or screening algorithm existed for unspecified mood disorder and disruptive mood dysregulation disorder, these conditions were caregiver-reported and working diagnoses for 11.7% (27/231) and 16.8% (25/149) of individuals, respectively. CONCLUSIONS Caregivers described Sources of Distress as an acceptable tool for sharing their knowledge and insights about individuals with DD who present in crisis. As a screening tool, this survey demonstrates good accuracy. However, better differentiation among mood disorders is needed, including the addition of items and screening algorithm for unspecified mood disorder and disruptive mood dysregulation disorder. Additional validation efforts are necessary to include a more geographically diverse population and reevaluate mood disorder differentiation. Future study is merited to investigate the survey’s impact on the psychiatric and medical management of distress in individuals with DD.