A framework for an evidence-based gene list relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mechanistic target of rapamycin (mTOR) overactivity. Limited data suggest that mTOR inhibitors may be therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism. We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5-45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners' Continuous Performance Test hit reaction time and Purdue Pegboard Test score. Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (P < 0.001). Changes in the primary endpoint between groups from baseline to Month 6 were not apparent (Cohen's d = -0.10, P = 0.518). However, several measures were associated with modest effect sizes (≥0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior and global improvement. There was a significant difference in EEG central alpha power (P = 0.049) and central beta power (P = 0.039) 6 months after everolimus treatment. Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.

Development of webcam-collected and artificial-intelligence-derived social and cognitive performance measures for neurodevelopmental genetic syndromes.

This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test-retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40-0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.

Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes.

There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations.

The Autism Symptom Dimensions Questionnaire: Development and psychometric evaluation of a new, open-source measure of autism symptomatology.

AIM: To describe the development and initial psychometric evaluation of a new, freely available measure, the Autism Symptom Dimensions Questionnaire (ASDQ). METHOD: After development and revision of an initial 33-item version, informants completed a revised 39-item version of the ASDQ on 1467 children and adolescents (aged 2-17 years), including 104 with autism spectrum disorder (ASD). RESULTS: The initial 33-item version of the ASDQ had good reliability and construct validity. However, only four specific symptom factors were identified, potentially due to an insufficient number of items. Factor analyses of the expanded instrument identified a general ASD factor and nine specific symptom factors with good measurement invariance across demographic groups. Scales showed good-to-excellent overall and conditional reliability. Exploratory analyses of predictive validity for ASD versus neurotypical and other developmental disability diagnoses indicated good accuracy for population and at-risk contexts. INTERPRETATION: The ASDQ is a free and psychometrically sound informant report instrument with good reliability of measurement across a continuous range of scores and preliminary evidence of predictive validity. The measure may be a useful alternative to existing autism symptom measures but further studies with comparison of clinical diagnoses using criterion-standard instruments are needed. WHAT THIS PAPER ADDS: The Autism Symptom Dimensions Questionnaire (ASDQ) is a new, freely available measure of autism symptoms. The ASDQ showed reliable and accurate measurement of autism symptoms. The measure had good screening efficiency for autism spectrum disorder relative to other developmental conditions.

Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome.

Germline heterozygous PTEN mutations cause subsets of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS); these subsets are characterized by high risks of breast, thyroid, and other cancers and, in one subset, autism spectrum disorder (ASD). Up to 10% of individuals with PTENMUT CS, CS-like syndrome, or BRRS have germline SDHx (succinate dehydrogenase, mitochondrial complex II) variants, which modify cancer risk. PTEN contributes to metabolic reprogramming; this is a well-established role in a cancer context. Relatedly, SDH sits at the crossroad of the electron transport chain and tricarboxylic acid (TCA) cycle, two central bioenergetic pathways. Intriguingly, PTENMUT and SDHMUT individuals have reduced SDH catalytic activity, resulting in succinate accumulation; this indicates a common genotype-independent biochemical alteration. Here, we conducted a TCA targeted metabolomics study on 511 individuals with CS, CS-like syndrome, or BRRS with various genotypes (PTEN or SDHx, mutant or wild type [WT]) and phenotypes (cancer or ASD) and a series of 187 population controls. We found consistent TCA cycle metabolite alterations in cases with various genotypes and phenotypes compared to controls, and we found unique correlations of individual metabolites with particular genotype-phenotype combinations. Notably, increased isocitrate (p = 1.2 × 10-3), but reduced citrate (p = 5.0 × 10-4), were found to be associated with breast cancer in individuals with PTENMUT/SDHxWT. Conversely, increased lactate was associated with neurodevelopmental disorders regardless of genotype (p = 9.7 × 10-3); this finding was replicated in an independent validation series (n = 171) enriched for idiopathic ASD (PTENWT, p = 5.6 × 10-4). Importantly, we identified fumarate (p = 1.9 × 10-2) as a pertinent metabolite, distinguishing individuals who develop ASD from those who develop cancer. Our observations suggest that TCA cycle metabolite alterations are germane to the pathobiology of PTEN-related CS and BRRS, as well as genotype-independent ASD, with implications for potential biomarker and/or therapeutic value.

Outcomes of Abbreviated MRI (Ab-MRI) for Women of any Breast Cancer Risk and Breast Density in a Community Academic Setting.

BACKGROUND: Abbreviated magnetic resonance imaging (Ab-MRI) has been evaluated for elevated breast cancer risk or dense breasts but has not been evaluated across all risk profiles. METHODS: Patients selected underwent Ab-MRI from February 2020 to September 2021. Women were older than aged 30 years, up to date with screening mammography, and paid $299 cash. RESULTS: A total of 93 patients were identified with a mean age of 52 years; 92.5% were Caucasian, 0% black, and 97.9% were from high socioeconomic status. Mean Gail score was 14.2, and 83.3% had a lifetime risk of breast cancer <20%. Reasons for Ab-MRI: dense breasts (36.6%); family history (24.7%); palpable mass (12.9%). Providers ordering: OBGYN (49.5%); breast surgeon (39.1%); primary care (6.6%). Thirteen biopsies (14%) detected one breast cancer. 31.1% had a change in follow-up screening: 58.6% 6-month MRI, 20.7% 6-month mammogram, and 10.3% 6-month ultrasound. Negative predictive value was 100% (95% confidence interval [CI]: 95-100%, p < 0.0001). Sensitivity was 100% (95% CI: 2.5-100%, p < 0.0001), and specificity was 87% (95% CI: 78.3-93.1%, p < 0.0001) compared with 77.6% and 98.8% for mammography. Only one cancer was detected: cost of $27,807 plus cost of 13 MRI or ultrasound (US)-guided biopsies and additional follow-up imaging. Historically 20% of abnormalities detected on full MRI are malignant; however, 7.7% of ab-MRI abnormalities were malignant CONCLUSIONS: One third of women were recommended a change in follow-up, which predominantly included a 6-month MRI. Ab-MRI may introduce average risk women to unnecessary follow-up and increased biopsies with a lower cancer detection rate. Ab-MRI should be evaluated closely before implementation.

Tackling healthcare access barriers for individuals with autism from diagnosis to adulthood.

Most individuals with autism spectrum disorder (ASD)-a complex, life-long developmental disorder-do not have access to the care required to address their diverse health needs. Here, we review: (1) common barriers to healthcare access (shortage/cost of services; physician awareness; stigma); (2) barriers encountered primarily during childhood (limited screening/diagnosis; unclear referral pathways), transition to adulthood (insufficient healthcare transition services; suboptimal physician awareness of healthcare needs) and adulthood (shortage of services/limited insurance; communication difficulties with physicians; limited awareness of healthcare needs of aging adults); and (3) advances in research/program development for better healthcare access. A robust understanding of barriers to accessing healthcare across the lifespan of autistic individuals is critical to ensuring the best use of healthcare resources to improve social, physical, and mental health outcomes. Stakeholders must strengthen healthcare service provision by coming together to: better understand healthcare needs of underserved populations; strengthen medical training on care of autistic individuals; increase public awareness of ASD; promote research into/uptake of tools for ASD screening, diagnosis, and treatment; understand specific healthcare needs of autistic individuals in lower resource countries; and conduct longitudinal studies to understand the lifetime health, social, and economic impacts of ASD and enable the evaluation of novel approaches to increasing healthcare access. IMPACT: Despite the growing body of evidence, our understanding of barriers to healthcare encountered by individuals with ASD remains limited, particularly beyond childhood and in lower resource countries. We describe current and emerging barriers to healthcare access encountered by individuals with ASD across the lifespan. We recommend that stakeholders develop evidence-informed policies, programs, and technologies that address barriers to healthcare access for individuals with ASD and consider broad, equitable implementation to maximize impact.

Metabolic Syndrome: does this influence breast cancer outcomes in the triple-negative population?

INTRODUCTION: Metabolic syndrome (MS) is defined by having at least 3 of 4 components: obesity, dyslipidemia, hypertension (HTN), and diabetes. Prior studies analyzed the individual components of MS for all breast cancers which are predominantly hormone positive. Our study is the first to evaluate MS in triple-negative breast cancer (TNBC). METHODS: A retrospective review of TNBC from 2007 to 2013 identified 177 patients with complete information for statistical analysis. Cox proportional hazards models were used to test the association between MS, disease-free survival (DFS), and overall survival (OS). RESULTS: 48 (27%) patients had MS. After controlling for age, race, pathologic stage, surgery type, and additional comorbidities outside of MS, MS was significantly associated with poorer DFS (adjusted HR: 2.24, p = 0.030), but not associated with OS (adjusted HR: 1.92, p = 0.103). HTN was significantly associated with poorer DFS (adjusted HR: 3.63, p = 0.006) and OS (adjusted HR: 3.45, p = 0.035) in the univariable and multivariable analyses. Diabetes was not associated with worse OS or DFS. The 5-year age-adjusted OS rates for 60-year-old patients with and without diabetes were 85.8% and 87.3%, respectively. The age-adjusted 5-year OS rate for 60-year old patients was higher in patients with a body mass index (BMI) > 30 (90.2%) versus BMIs of 25-29.9 (88.2%) or < 25 (83.5%). CONCLUSION: In the TNBC population, MS was significantly associated with poorer DFS, but not associated with OS. HTN was the only component of MS that was significantly associated with both DFS and OS. Obesity has a potential small protective benefit in the TNBC population.

COVID-19 Pandemic: Changes in Care for a Community Academic Breast Center and Patient Perception of Those Changes.

BACKGROUND: Philadelphia and its suburbs were an epicenter for the initial COVID-19 outbreak. Accordingly, alterations were made in breast cancer care at a community hospital. METHODS: The authors developed a prospective database of all the patients with invasive or in situ breast cancer between March 1 and June 15 at their breast center. Any change in a breast cancer plan due to the pandemic was documented, and the patients were grouped into two cohorts according to whether a change was made (CTX) or no change was made (NC) in their care. The patients were asked a series of questions about their care, including those in the Generalized Anxiety Disorder two-item questionnaire (GAD-2), via telephone. RESULTS: The study enrolled 73 patients: 41 NC patients (56%) and 32 CTX patients (44%). The two cohorts did not differ in terms of age, race, or stage. Changes included delay in therapy (15.1%) and use of neoadjuvant endocrine therapy (NET, 28.8%). The median time to surgery was 24 days (interequartile range [IQR], 16-45 days) for the NC patients and 82 day s (IQR, 52-98 days) for the CTX patients (p ≤ 0.001). The median duration of NET was 78 days. The GAD-2 showed anxiety positivity to be 29.6% for the CTX patients and 32.4% for the NC patients (p = 1.00). More than half (55.6%) of the CTX patients believed COVID-19 affected their treatment outlook compared with 25.7% of the NC patients (p = 0.021). CONCLUSIONS: A prospective database captured changes in breast cancer care at a community academic breast center during the initial phase of the COVID-19 pandemic. 44% of patients experienced a change in breast cancer care due to COVID-19. The same level of anxiety and depression was seen in both change in therapy (CTX) and no change (NC). 55.6% of CTX cohort believed COVID-19 affected their treatment outlook.

Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations.

This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage  = 8.93 years, SDage  = 4.75), 25 Macro-ASD (Mage  = 11.99 years; SDage  = 5.15), and 23 PTEN-No ASD (Mage  = 8.94 years; SDage  = 4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2  = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2  = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2  = 0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

Evaluating and Validating GBI Mania and Depression Short Forms for Self-Report of Mood Symptoms.

Objective: To evaluate short forms of free self-report mania and depression scales, evaluating their reliability, content coverage, criterion validity, and diagnostic accuracy.Method: Youths age 11 to 18 years seeking outpatient mental health services at either an Academic medical clinic (N = 427) or urban Community mental health center (N = 313), completed the General Behavior Inventory (GBI) and other rating scales. Youths and caregivers completed semi-structured interviews to establish diagnoses and mood symptom severity, with GBI scores masked during diagnosis. Ten- and seven-item short forms, psychometric projections, and observed performance were tested first in the Academic sample and then externally cross-validated in the Community sample.Results: All short forms maintained high reliability (all alphas >.80 across both samples), high correlations with the full-length scales (r.85 to.96), excellent convergent and discriminant validity with mood, behavior, and demographic criteria, and diagnostic accuracy undiminished compared to using the full-length scales. Ten-item scales showed advantages in terms of coverage; the 7 Up showed slightly weaker performance.Conclusions: Present analyses evaluated and externally cross-validated short forms that maintain high reliability and content coverage, and show strong criterion validity and diagnostic accuracy - even when used in an independent sample with very different demographics and referral patterns. The short forms appear useful in clinical applications including initial evaluation, as well as in research settings where they offer an inexpensive quantitative score. Short forms are available in more than two dozen languages. Future work should further evaluate sensitivity to treatment effects and cultural invariance.

Quantifying Research Domain Criteria Social Communication Subconstructs Using the Social Communication Questionnaire in Youth.

Research Domain Criteria (RDoC) has posited a set of social dimensions that could be useful in identifying sources of individual variation in social impairments across neurodevelopmental disorders. The current investigation aimed to derive estimates of the RDoC social constructs from the Social Communication Questionnaire (SCQ) and examine whether RDoC social processes, as captured by the SCQ, are best represented by a dimensional, categorical, or hybrid model. Individual SCQ items from 4 databases were combined resulting in a total of 26,407 individuals (Mage = 8.13 years, SDage = 4.19; 69.1% male). The sample consisted of 60.0% of individuals with autism spectrum disorder (ASD), 6.8% with a range of neurodevelopmental disorders and 33.2% of siblings of individuals with ASD. Comparison of a range of factor solutions through the use of exploratory structural equation modeling and confirmatory factor analysis indicated that a 3-factor structure with separate attachment and affiliation, production of nonfacial and facial communication factors provided excellent fit to the data (comparative fit index = .989, Tucker-Lewis index = .984, root mean square error of approximation = .045). and robustness across clinical groups, age, sex, and verbal status. Comparison between the best-fitting factor analysis, latent class analysis, and factor mixture analysis solutions demonstrated that the RDoC social processes domain is best represented as dimensional. Our findings show promise for capturing some of the important RDoC social constructs using the SCQ but also highlight crucial areas for the development of new, dedicated dimensional measures.

Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Developing and Validating Short Forms of the Parent General Behavior Inventory Mania and Depression Scales for Rating Youth Mood Symptoms.

To develop short forms of parent-rated mania and depression scales, evaluating their reliability, content coverage, criterion validity, and diagnostic accuracy. Caregivers completed the Parent General Behavior Inventory about their youth 5-18 years of age seeking outpatient mental health services at either an academic medical clinic (n = 617) or urban community mental health center (n = 530), along with other rating scales. Families also completed a semistructured Kiddie Schedule for Affective Disorders and Schizophrenia interview, with the rating scales masked during diagnosis. Ten-item short forms and projections of their psychometrics (vs. the full-length 46-item Depression and 28-item Hypomanic/Biphasic scales) were built in the academic sample and then externally cross-validated in the community sample. The mania and two depression short forms maintained high reliability (αs > .87 across both samples); high correlations with the full-length scales (rs> .93); excellent convergent and discriminant validity with mood, behavior, and demographic criteria; and diagnostic accuracy undiminished compared to using the full-length scales. Present analyses developed and externally cross-validated 10-item short forms that maintain high reliability and content coverage and show strong criterion validity and diagnostic accuracy-even when used in an independent sample with markedly different demographics and referral patterns. The short forms appear useful in clinical applications, including screening and initial evaluation, as well as in research settings, where they offer an inexpensive quantitative score. Future work should further evaluate sensitivity to treatment effects. The short forms are available in more than a dozen translations.

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

PURPOSE: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. METHODS: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. RESULTS: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%). CONCLUSION: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

Perceived barriers to medication adherence remain stable following solid organ transplantation.

Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post-transplant while their guardians completed PMBS. Differences over time for pre-identified AMBS/PMBS factors were analyzed. Perceived barrier reporting impact on subsequent TAC levels was assessed. A total of 123 patients or their guardians completed PMBS or AMBS. Twenty-six were 6-11 years and 97 were ≥12. The final cohort consisted of kidney (66%), lung (19%), liver (8%), and heart (7%) recipients. Unadjusted analysis showed no statistically significant change in reported barriers from visit 1 (median 2.6 months, range 1.2-3.7 post-transplant) to visit 2 (median 12, range 8.9-16.5). Of 102 patients with TAC levels, 74 had a single level reported at both visits. The factor of "Disease frustration" was identified through the PMBS/AMBS questions about fatigue around medication and disease. Each point increase in "disease frustration" at visit 1 on the AMBS/PMBS doubled the odds of a lower-than-threshold TAC level at visit 2. No clear change in overall level of perceived barriers to medication adherence in the first year post-transplant was seen in pediatric SOT. However, disease frustration early post-transplant was associated with a single subtherapeutic TAC levels at 12 months. A brief screening measure may allow for early self-identification of risk.

Is the Finding Too Good to Be True? Moving from "More Is Better" to Thinking in Terms of Simple Predictions and Credibility.

In 2018, De Los Reyes and Langer expanded the scope of the Evidence Base Updates series to include reviews of psychological assessment techniques. In keeping with the goal of offering clear "take-home messages" about the evidence underlying the technique, experts have proposed a rubric for evaluating the reliability and validity support. Changes in the research environment and pressures in the peer review process, as well as a lack of familiarity with some statistical methods, have created a situation in which many findings that appear "excellent" in the rubric are likely to be "too good to be true," in the sense that they are unlikely to generalize to clinical settings or are unlikely to be reproduced in independent samples. We describe several common scenarios in which published results are often too good to be true, including internal consistency, interrater reliability, correlation, standardized mean differences, diagnostic accuracy, and global model fit statistics. Simple practices could go a long way toward improving design, reporting, and interpretation of findings. When effect sizes are in the "excellent" range for issues that have been challenging, scrutinize before celebrating. When benchmarks are available based on theory or meta-analyses, results that are moderately better than expected in the favorable direction (i.e., Cohen's q ≥ +.30) also invite critical appraisal and replication before application. If readers and reviewers pull for transparency and do not unduly penalize authors who provide it, then change in research quality will be faster and both generalizability and reproducibility are likely to benefit.

Diagnostic Accuracy of the CASI-4R Psychosis Subscale for Children Evaluated in Pediatric Outpatient Clinics.

Diagnostic accuracy of the Diagnostic and Statistical Manual of Mental Disorders-oriented Child and Adolescent Symptom Inventory (CASI-4R) Psychotic Symptoms scale was tested using receiver operating characteristic analyses to identify clinically significant psychotic symptoms. Participants were new outpatients (N = 700), ages 6.0 to 12.9 years (M = 9.7, SD = 1.8) at 9 child outpatient mental health clinics, who participated in the Longitudinal Assessment of Manic Symptoms (LAMS) Study baseline assessment. Because LAMS undersampled participants with low mania scores by design, present analyses weighted low scorers to produce unbiased estimates. Psychotic symptoms, operationally defined as a score of 3 or more for hallucinations or 4 or more for delusions based on the Schedule for Affective Disorders and Schizophrenia (K-SADS) psychosis items, occurred in 7% of youth. K-SADS diagnoses for those identified with psychotic symptoms above threshold included major depressive disorder, bipolar spectrum disorder, attention deficit/hyperactivity disorder, posttraumatic stress disorder, psychotic disorders, and autism spectrum disorder. The optimal psychosis screening cut score (maximizing sensitivity and specificity) was 2.75+ (corresponding diagnostic likelihood ratio [DiLR] = 4.29) for the parent version and 3.50+ (DiLR = 5.67) for the teacher version. The Area under the Curve for parent and teacher report was .83 and .74 (both p < .001). Parent report performed significantly better than teacher report for identifying psychotic symptoms above threshold (p = .03). The CASI-4R Psychosis subscale (J) appears clinically useful for identifying psychotic symptoms in children because of its brevity and accuracy.