Pancreatic Replacement Therapy for Maladaptive Behaviors in Preschool Children With Autism Spectrum Disorder.

Importance: There is an urgent unmet need for a treatment addressing the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in preschool populations. Objectives: To evaluate whether treatment of children with ASD aged 3 to 6 years treated with high-protease pancreatic therapy produces long- and short-term improvements in autism-associated maladaptive behaviors. Design, Setting, and Participants: This cohort study at 32 sites across the US used a double-blind parallel group, delayed-start design comprising a 2-week blinded placebo run-in, and a double-blind, randomized, placebo-controlled segment (12 weeks). Children were recruited into the study in 2015, with data collection continuing until 2021. The analyses were completed from June 2021 to February 2022. Interventions: All participants were randomly assigned to receive either 900 mg high-protease pancreatic replacement therapy or placebo with food 3 times a day for 12 weeks, followed by all receiving 900 mg high-protease pancreatic replacement therapy for 24 weeks. Main Outcomes and Measures: The primary outcome was the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I). All potential participants were screened using the Social Communication Questionnaire (SCQ) with diagnosis confirmed by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) for ASD and the Autism Diagnostic Inventory-Revised (ADI-R). Outcomes were measured at the conclusion of the 12-week double-blind segment and at the conclusion of the 24-week open-label segment (total 36 weeks). Results: A total of 190 participants (150 male [79%]), aged 3 to 6 (mean [SD] age, 4.5 [0.8]) years were randomized. Mixed model for repeated measures analysis performed on ABC-I demonstrated statistically significant differences of -2.49 (95% CI, -4.66 to -0.32; Cohen d = 0.364; P = .03) at the 12-week timepoint and -3.07 (95% CI, -5.81 to -0.33; Cohen d = 0.516; P = .03) at 36-week timepoint. No convergence was noted. Our high-protease pancreatic replacement (CM-AT) was well tolerated with no emergent safety concerns or related serious adverse events noted. Conclusions and Relevance: This cohort study of preschool children sustained cumulative reduction in the maladaptive behavior of irritability in autism. This delayed-start analysis, used to demonstrate disease and condition modification, may prove to be an important tool to evaluate treatments for ASD. Trial Registration: ClinicalTrials.gov Identifier: NCT02410902 and NCT02649959.

Autism Spectrum Disorder and Complementary-Integrative Medicine.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects 0.6%-1.7% of children. The etiology of autism is hypothesized to include both biological and environmental factors (Watts, 2008). In addition to the core symptoms of social-communication delay and restricted, repetitive interests, co-occurring irritability/aggression, hyperactivity, and insomnia negatively impact adaptive functioning and quality of life of patients and families. Despite years of effort, no pharmacologic agent has been found that targets the core symptoms of ASD. The only FDA-approved agents are risperidone and aripiprazole for agitation and irritability in ASD, not for core symptoms. Though they effectively reduce irritability/violence, they do so at the expense of problematic side effects: metabolic syndrome, elevated liver enzymes, and extrapyramidal side effects. Thus, it is not surprising that many families of children with ASD turn to nonallopathic treatment, including dietary interventions, vitamins, and immunomodulatory agents subsumed under complementary-integrative medicine (CIM). Per recent studies, 27% to 88% of families report using a CIM treatment. In an extensive population-based survey of CIM, families of children with more severe ASD, comorbid irritability, GI symptoms, food allergies, seizures, and higher parental education tend to use CIM at higher rates. The perceived safety of CIM treatments as "natural treatment" over allopathic medication increases parental comfort in using these agents. The most frequently used CIM treatments include multivitamins, an elimination diet, and Methyl B12 injections. Those perceived most effective are sensory integration, melatonin, and antifungals. Practitioners working with these families should improve their knowledge about CIM as parents currently perceive little interest in and poor knowledge of CIM by physicians. This article reviews the most popular complementary treatments preferred by families with children with autism. With many of them having limited or poor quality data, clinical recommendations about the efficacy and safety of each treatment are discussed using the SECS versus RUDE criteria.

The Associations Between Sluggish Cognitive Tempo, Internalizing Symptoms, and Academic Performance in Children With Reading Disorder: A Longitudinal Cohort Study.

OBJECTIVE: To investigate whether sluggish cognitive tempo (SCT) was associated with anxiety, depression, and academic performance (AP) in children with reading disorder (RD), and whether ADHD-Inattention (ADHD-IN) moderated these relationships. METHOD: Parents and teachers of children with RD (N = 147, ages 6-18) completed evaluations of SCT, ADHD, anxiety, depression, and AP, every 3 months for 18 months. Baseline and longitudinal associations between SCT and outcomes, and effect moderation of ADHD-IN, were assessed. RESULTS: Teacher-rated SCT was positively associated with teacher-rated anxiety (p < .001) and negatively associated with AP (p < .001) cross-sectionally and longitudinally, with significant effect modification by ADHD-IN for both outcomes. SCT was not associated with depression in adjusted cross-sectional and longitudinal analyses. There were no significant findings for any parent-reported measures. CONCLUSION: SCT has negative effects on anxiety and AP in children with RD among individuals with low ADHD-IN according to teacher report. Targeted treatment of SCT may provide substantial benefits.

A systematic review and meta-analysis of the benefits of a gluten-free diet and/or casein-free diet for children with autism spectrum disorder.

CONTEXT: It has been suggested that a gluten-free and casein-free (GFCF) diet may alleviate the symptoms of autism spectrum disorder (ASD) and facilitate neurodevelopment of children with ASD. Studies to date have been inconclusive. OBJECTIVE: This study aimed to evaluate (through quantitative meta-analysis) the efficacy and safety of a GFCF diet for children with ASD. To our knowledge, this is the first time such an analysis has been carried out. DATA SOURCES: Eight electronic databases were searched, from the establishment of each database up to March 27, 2020: PubMed, Web of Science, Embase (Ovid), PsycINFO (Ovid), Cochrane Library, CNKI, Wanfang, and VIP databases. DATA EXTRACTION: Two authors independently performed the data extraction and risk-of-bias assessment. DATA ANALYSIS: A quantitative meta-analysis was performed with standard procedures by using Stata SE 15 software. Within the total of 8 studies, with 297 participants, 5 studies reported significant reductions in stereotypical behaviors [standard mean difference (SMD) = -0.41, 95% confidence interval (CI): -0.68 to -0.15], and 3 studies reported improvements in cognition (SMD = -0.46, 95% CI: -0.91 to -0.01) following GFCF dietary intervention . No statistically significant changes were observed in other symptomatic categories (all P > 0.05). CONCLUSION: The current meta-analysis showed that a GFCF diet can reduce stereotypical behaviors and improve the cognition of children with ASD. Though most of the included studies were single-blind, the benefits of a GFCF diet that have been indicated are promising. Additional studies on a larger scale are warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020177619.

The role of grit and resilience in children with reading disorder: a longitudinal cohort study.

Prior studies have suggested that grit and resilience predict both academic and career success. However, these qualities have not been examined in children with reading disorder (RD). We therefore investigated whether grit and resilience were associated with anxiety, depression, academic performance, and quality of life (QOL) in these students. This 3-year longitudinal cohort study included 163 participants with RD from 3 schools. Evaluations were completed by parents and/or teachers every 3 months. The Grit and Resilience Scale was adapted from the 10-item Connor-Davidson Resilience Scale and the 12-item Grit Scale. Outcome measures included anxiety (School Anxiety Scale - Teacher Report and the 8-item Spence Children's Anxiety Scale), depression (Short Mood and Feelings Questionnaire), academic performance, and QOL (Pediatric QOL Inventory 4.0). Multivariate linear regression models (adjusting for age and sex) assessed the associations at baseline. Repeated measures analysis using mixed-effects models assessed the relationship longitudinally. There were statistically significant associations between grit and resilience and all outcomes at baseline and over time. After adjusting for age and sex, improved grit and resilience was associated with decreased anxiety (ß = - 0.4, p < 0.001) and improved academic performance (ß = 0.5, p < 0.001) when grit and resilience was measured by teachers, as well as decreased depression (ß = - 0.3, p < 0.001) and improved QOL (ß = 0.6, p < 0.001) when grit and resilience was measured by parents. Grit and resilience are significantly related to mental health, academic performance, and QOL in children with RD. This suggests that interventions to improve grit and resilience may lead to positive benefits.

Editorial: Addressing the "Cliff" for Adults With Autism Spectrum Disorder.

Parents of young children diagnosed with autism spectrum disorder (ASD) desperately search for a cure for their child's disorder. Depending on their child's severity or lack of progress, parents shift from looking for a cure to finding arrangements where their child can live a fulfilling life as an adult when they are less involved and less able to help. Sadly, they too often find that the resources they have fought for their children to receive disappear when their youngsters leave school.

Editorial: What to Do About Rigid, Repetitive Behaviors in Autism Spectrum Disorder?

Rigid, repetitive behaviors (RRBs) as a part of autism spectrum disorder (ASD) are perplexing and challenging to treat effectively. First, how is it that they associate with deficits in social communication and social interaction to create a strong symptomatic association for the DSM-5 diagnosis of ASD?1 Deficits in social communication make sense in how they define a developmental disorder, but what is the mechanism by which social interaction and RRBs connect to define the classification of ASD? Perhaps it is that, rather than by neurotransmitters or linked structural brain regions, ASD is a neural systems condition mediated by abnormalities in regionally distributed cortical networks.2.

Social attention to activities in children and adults with autism spectrum disorder: effects of context and age.

BACKGROUND: Diminished visual monitoring of faces and activities of others is an early feature of autism spectrum disorder (ASD). It is uncertain whether deficits in activity monitoring, identified using a homogeneous set of stimuli, persist throughout the lifespan in ASD, and thus, whether they could serve as a biological indicator ("biomarker") of ASD. We investigated differences in visual attention during activity monitoring in children and adult participants with autism compared to a control group of participants without autism. METHODS: Eye movements of participants with autism (n = 122; mean age [SD] = 14.5 [8.0] years) and typically developing (TD) controls (n = 40, age = 16.4 [13.3] years) were recorded while they viewed a series of videos depicting two female actors conversing while interacting with their hands over a shared task. Actors either continuously focused their gaze on each other's face (mutual gaze) or on the shared activity area (shared focus). Mean percentage looking time was computed for the activity area, actors' heads, and their bodies. RESULTS: Compared to TD participants, participants with ASD looked longer at the activity area (mean % looking time: 58.5% vs. 53.8%, p < 0.005) but less at the heads (15.2% vs. 23.7%, p < 0.0001). Additionally, within-group differences in looking time were observed between the mutual gaze and shared focus conditions in both participants without ASD (activity: Δ = - 6.4%, p < 0.004; heads: Δ = + 3.5%, p < 0.02) and participants with ASD (bodies: Δ = + 1.6%, p < 0.002). LIMITATIONS: The TD participants were not as well characterized as the participants with ASD. Inclusion criteria regarding the cognitive ability [intelligence quotient (IQ) > 60] limited the ability to include individuals with substantial intellectual disability. CONCLUSIONS: Differences in attention to faces could constitute a feature discriminative between individuals with and without ASD across the lifespan, whereas between-group differences in looking at activities may shift with development. These findings may have applications in the search for underlying biological indicators specific to ASD. Trial registration ClinicalTrials.gov identifier NCT02668991.

Quality of Life Among School-Age Children With Autism: The Oak Hill School Outcomes Study.

Prior studies have documented a lower quality of life (QOL) in children with autism spectrum disorder (ASD) compared to typically developing peers, but few studies have examined the trajectory of QOL over time in the same population. We conducted a 2-year cohort study in 29 children attending a specialized school for ASD with quarterly measures of parent-rated QOL as well as parent and teacher measures of behavior and social skills to determine the trajectory of change in QOL and predictors of change. The average change in QOL was constant (no change over time), but there was substantial variation with some students showing significant gains and others showing declines. Exploratory analyses revealed that improvements in behavior and social skills were greater (nonsignificantly) among children with improvements in QOL. Children with improved QOL were also younger and had a lower initial symptom burden. This study suggests that early intervention programs that provide social skills and behavioral management strategies may improve QOL in children with ASD. The study also highlights the need to develop and study novel, qualitative measures of QOL in this population.

Dietary Interventions for Autism Spectrum Disorder: A Meta-analysis.

CONTEXT: Dietary interventions such as restrictive diets or supplements are common treatments for young people with autism spectrum disorder (ASD). Evidence for the efficacy of these interventions is still controversial. OBJECTIVE: To assess the efficacy of specific dietary interventions on symptoms, functions, and clinical domains in subjects with ASD by using a meta-analytic approach. DATA SOURCES: Ovid Medline, PsycINFO, Embase databases. STUDY SELECTION: We selected placebo-controlled, double-blind, randomized clinical trials assessing the efficacy of dietary interventions in ASD published from database inception through September 2017. DATA EXTRACTION: Outcome variables were subsumed under 4 clinical domains and 17 symptoms and/or functions groups. Hedges' adjusted g values were used as estimates of the effect size of each dietary intervention relative to placebo. RESULTS: In this meta-analysis, we examined 27 double-blind, randomized clinical trials, including 1028 patients with ASD: 542 in the intervention arms and 486 in the placebo arms. Participant-weighted average age was 7.1 years. Participant-weighted average intervention duration was 10.6 weeks. Dietary supplementation (including omega-3, vitamin supplementation, and/or other supplementation), omega-3 supplementation, and vitamin supplementation were more efficacious than the placebo at improving several symptoms, functions, and clinical domains. Effect sizes were small (mean Hedges' g for significant analyses was 0.31), with low statistical heterogeneity and low risk of publication bias. LIMITATIONS: Methodologic heterogeneity among the studies in terms of the intervention, clinical measures and outcomes, and sample characteristics. CONCLUSIONS: This meta-analysis does not support nonspecific dietary interventions as treatment of ASD but suggests a potential role for some specific dietary interventions in the management of some symptoms, functions, and clinical domains in patients with ASD.

Improving autism perinatal risk factors: A systematic review.

BACKGROUND: Current understanding of the etiology of autism is based on the interaction of multiple genes with each other and with environmental factors, leading to a neurodevelopmental process that results in the expression of autism spectrum disorder (ASD) in the child. This suggests that it might be possible to strengthen resilience to environmental stressors during the perinatal period to improve outcomes and possibly prevent the development of ASD. METHODS: We searched the MEDLINE database for multiple perinatal factors associated with the development of ASD published between January 1, 2005 and July 1, 2018. The search terms used were "autism" crossed with either "perinatal," "prenatal," "gestational," or "pregnancy," and crossed again with each perinatal risk factor highlighted in this review including topics on parental health, infections, medications, and environmental stressors. We then searched interventions that may improve neurodevelopmental outcome before and during pregnancy, including supplements, breastfeeding, and postpartum stress reduction. We identified recent or unique metanalyses and systematic reviews of the identified focus and on randomized controlled trials and summarized these using the most recent and comprehensive reviews. RESULTS: Folate, omega-3, vitamin D3, environmental toxin avoidance, correcting deficiencies, immune boosting, and prolonged breast feeding are all reported to be linked to the possible reduction of adverse pregnancy outcomes including ASD. CONCLUSIONS: Studies of individual components for improving pregnancy outcomes and several uncontrolled preconception to infancy medical practices suggest that multiple interventions might improve the outcomes of pregnancies where there is risk for developing ASD.

Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies.

Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

Anxiety and Attentional Bias in Children with Specific Learning Disorders.

Children with specific learning disorders (SLDs) face a unique set of socio-emotional challenges as a result of their academic difficulties. Although a higher prevalence of anxiety in children with SLD is often reported, there is currently no research on cognitive mechanisms underlying this anxiety. One way to elucidate these mechanisms is to investigate attentional bias to threatening stimuli using a dot-probe paradigm. Our study compared children ages 9-16 with SLD (n = 48) to typically-developing (TD) controls (n = 33) on their attentional biases to stimuli related to general threats, reading, and stereotypes of SLD. We found a significant threat bias away from reading-related stimuli in the SLD, but not TD group. This attentional bias was not observed with the general threat and stereotype stimuli. Further, children with SLD reported greater anxiety compared to TD children. These results suggest that children with SLD experience greater anxiety, which may partially stem from reading specifically. The finding of avoidance rather than vigilance to reading stimuli indicates the use of more top-down attentional control. This work has important implications for therapeutic approaches to anxiety in children with SLD and highlights the need for attention to socio-emotional difficulties in this population. Future research is needed to further investigate the cognitive aspects of socio-emotional difficulties in children with SLD, as well as how this may impact academic outcomes.

Considerations from the 2017 IMFAR Preconference on Measuring Meaningful Outcomes from School-Age to Adulthood.

The autism spectrum disorder (ASD) research community is increasingly considering the importance of measuring outcomes that are meaningful to individuals with ASD and their families. The 2017 IMFAR preconference aimed to gain the perspectives of how to define and measure "meaningful outcomes" from 280 participants, including people with ASD and their families, service providers, and researchers. Six themes were identified: (a) the definition of "outcome" varies by context and perspective; (b) the need to broaden the scope of what researchers measure; (c) the need for new assessment tools; (d) the need to expand data analytic methods; (e) where to focus (with emphasis on considering different developmental stages and aspects of diversity); and (f) a need for community partnerships to bridge research and daily practice. The challenge that the research community now faces is how to move the evidence base for clinical practice forward while keeping alive the divergence of views and considerations that are relevant for thinking about complex outcomes for the highly heterogeneous group of individuals with ASD. This commentary provides recommendations, with an emphasis on lifespan viewpoints that encompass individual strengths and preferences. Autism Research 2018, 11: 1446-1454. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The 2017 IMFAR preconference aimed to gain the perspectives of how to define and measure "meaningful outcomes" from a variety of stakeholders. This commentary outlines the six themes identified from keynote and panel presentations and audience-participated discussions. Recommendations are made to emphasize perspectives that look across the lifespan and encompass individual strengths and preferences.

Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli.

Background: Children with autism spectrum disorder (ASD) have urinary metabolites suggesting impairments in several pathways, including oxidative stress, inflammation, mitochondrial dysfunction, and gut microbiome alterations. Sulforaphane, a supplement with indirect antioxidant effects that are derived from broccoli sprouts and seeds, was recently shown to lead to improvements in behavior and social responsiveness in children with ASD. We conducted the current open-label study to determine if we could identify changes in urinary metabolites that were associated with clinical improvements with the goal of identifying a potential mechanism of action. Methods: Children and young adults enrolled in a school for children with ASD and related neurodevelopmental disorders were recruited to participate in a 12-week, open-label study of sulforaphane. Fasting urinary metabolites and measures of behavior (Aberrant Behavior Checklist-ABC) and social responsiveness (Social Responsiveness Scale-SRS) were measured at baseline and at the end of the study. Pearson's correlation coefficient was calculated for the pre- to post-intervention change in each of the two clinical scales (ABS and SRS) versus the change in each metabolite. Results: Fifteen children completed the 12-week study. Mean scores on both symptom measures showed improvements (decreases) over the study period, but only the change in the SRS was significant. The ABC improved - 7.1 points (95% CI - 17.4 to 3.2), and the SRS improved - 9.7 points (95% CI - 18.7 to - 0.8). We identified 77 urinary metabolites that were correlated with changes in symptoms, and they clustered into pathways of oxidative stress, amino acid/gut microbiome, neurotransmitters, hormones, and sphingomyelin metabolism. Conclusions: Urinary metabolomics analysis is a useful tool to identify pathways that may be involved in the mechanism of action of treatments targeting abnormal physiology in ASD. Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02654743) on January 11, 2016.

Recognizing Psychiatric Comorbidity With Reading Disorders.

Reading disorder (RD), a specific learning disorder (SLD) of reading that includes impairment in word reading, reading fluency, and/or reading comprehension, is common in the general population but often is not comprehensively understood or assessed in mental health settings. In education settings, comorbid mental and associated disorders may be inadequately integrated into intervention plans. Assessment and intervention for RD may be delayed or absent in children with frequently co-occurring mental disorders not fully responding to treatment in both school and mental health settings. To address this oversight, this review summarizes current knowledge regarding RDs and common comorbid or co-occurring disorders that are important for mental health and school settings. We chose to highlight RD because it is the most common SLD, and connections to other often comorbid disorders have been more thoroughly described in the literature. Much of the literature we describe is on decoding-based RD (or developmental dyslexia) as it is the most common form of RD. In addition to risk for academic struggle and social, emotional, and behavioral problems, those with RD often show early evidence of combined or intertwined Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition childhood disorders. These include attention deficit hyperactivity disorder, anxiety and depression, disruptive, impulse-control, and conduct disorders, autism spectrum disorders, and other SLDs. The present review highlights issues and areas of controversy within these comorbidities, as well as directions for future research. An interdisciplinary, integrated approach between mental health professionals and educators can lead to comprehensive and targeted treatments encompassing both academic and mental health interventions. Such targeted treatments may contribute to improved educational and health-related outcomes in vulnerable youth. While there is a growing research literature on this association, more studies are needed of when to intervene and of the early and long-term benefits of comprehensive intervention.

Integrating Autism Care through a School-Based Intervention Model: A Pilot Study.

The purpose of this pilot study is to determine the feasibility of monitoring the progress of children with an autism spectrum disorder (ASD) both in school and at home to promote a school-based integrated care model between parents, teachers, and medical providers. This is a prospective cohort study. To monitor progress, outcome measures were administered via an online platform developed for caregivers and teachers of children (n = 30) attending a school specializing in neurodevelopmental disorders and using an integrated medical and education program. Longitudinal analysis showed improvements in a novel scale, the Teacher Autism Progress Scale (TAPS), which was designed to measure key autism-related gains in a school environment (2.1-point improvement, p = 0.004, ES = 0.324). The TAPS showed a strong and statistically significant correlation, with improvement in aberrant behavior (r = -0.50; p = 0.008) and social responsiveness (r = -0.70; p < 0.001). The results also showed non-statistically significant improvements in aberrant behavior, social responsiveness, and quality of life over time at both school and home. To assess feasibility of ongoing progress measurement, we assessed missing data, which showed caregivers were more likely to miss surveys during summer. Results demonstrate the value and feasibility of online, longitudinal data collection in school to assist with individualized education planning and collaborative care for children with ASD. Lessons learned in this pilot will support school outcomes researchers in developing more efficacious, collaborative treatment plans between clinicians, caregivers, and teachers.

Correction: Pleiotropic Mechanisms Indicated for Sex Differences in Autism.

[This corrects the article DOI: 10.1371/journal.pgen.1006425.].

Examining Clinics for Children with Autism: The Autism Translating To Treatment Study.

OBJECTIVES: Certain clinical providers specialize in providing complementary and integrative medicine (CIM) therapies for children with autism spectrum disorder (ASD). Because many of these providers and their patients/families have reported substantial improvement, the authors developed an online platform to carefully examine these clinical practices. The initial goal was to examine the feasibility of prospective data collection in this setting. The larger goals were to characterize the tests and treatments used in these clinics; examine associations between specific treatments, biomarkers, and improved outcomes; and identify promising treatments for future study. DESIGN: Prospective cohort study. SETTING: Four CIM clinics specializing in treating children with ASD. PATIENTS: Children with ASD age 2-8 years. INTERVENTIONS: The study protocol provided no interventions, but all interventions provided by the CIM clinical providers were recorded. OUTCOME MEASURES: Aberrant Behavior Checklist (ABC); Social Responsiveness Scale (SRS); and instruments that assessed sensory sensitivity, language, gastrointestinal (GI) symptoms, pediatric quality of life, and caregiver strain. RESULTS: Fourteen children were enrolled (mean age, 4.4 years). Over 3 months, the total behavior score (ABC) decreased (improved) from 110.8 to 103.8 (change, -7.0; 95% confidence interval [CI], -27.9 to 13.9), and the total social responsiveness score (SRS) decreased (improved) from 133.8 to 127.2 (change, -6.6; 95% CI, -30.5 to 17.3), but these changes were not statistically significant. Similarly, caregiver strain and pediatric quality of life decreased (improved) but by a nonsignificant amount. More severe GI symptoms and more severe ASD symptoms were associated with lower quality of life (p < 0.001). CONCLUSIONS: Barriers to successful data collection were identified. Despite these challenges, this study could confirm interesting associations between data elements, highlighting the future value of similar systems for improving evidence-based care in this population.