Validation of an ICD-Code-Based Case Definition for Psychotic Illness Across Three Health Systems.

BACKGROUND AND HYPOTHESIS: Psychosis-associated diagnostic codes are increasingly being utilized as case definitions for electronic health record (EHR)-based algorithms to predict and detect psychosis. However, data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. STUDY DESIGN: Using EHRs at 3 health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into 5 higher-order groups. 1133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. STUDY RESULTS: PPVs across all diagnostic groups and hospital systems exceeded 70%: Mass General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). CONCLUSIONS: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the case definitions used in the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Heterogeneity of clinical symptomatology in pediatric patients at clinical high risk for psychosis.

OBJECTIVE: Widespread use of diagnostic tools like the Structured Interview for Prodromal Symptoms (SIPS) has highlighted that youth at Clinical High Risk for Psychosis (CHR-P) present with heterogeneous symptomatology. This pilot study aims to highlight the range of clinical characteristics of CHR-P youth, investigate the role of the non-positive (negative, disorganization, and general) symptoms in risk assessment, and determine if specific profiles are associated with severe symptomatology. METHODS: 38 participants aged 7-18 were administered the SIPS and designated as CHR-P. Descriptive statistics and mean difference t-tests were used to describe the range in prevalence and severity of SIPS symptoms and to identify symptoms associated with greater overall symptomatology. RESULTS: Participants who had a greater number of positive symptoms also had significantly more negative, disorganization, and general symptoms. A number of SIPS symptoms were associated with greater number of positive symptoms. CONCLUSION: CHR-P youth represent a heterogeneous group, presenting with a wide range in clinical presentation as reflected in both the number of SIPS symptoms and their severity. Though the severity and duration of positive SIPS symptoms determines the CHR-P classification, high ratings on several of the other SIPS negative, disorganization, and general items may be useful indicators of elevated symptomatology.

Validation of an ICD-code-based case definition for psychotic illness across three health systems.

Background and Hypothesis: Early detection of psychosis is critical for improving outcomes. Algorithms to predict or detect psychosis using electronic health record (EHR) data depend on the validity of the case definitions used, typically based on diagnostic codes. Data on the validity of psychosis-related diagnostic codes is limited. We evaluated the positive predictive value (PPV) of International Classification of Diseases (ICD) codes for psychosis. Study Design: Using EHRs at three health systems, ICD codes comprising primary psychotic disorders and mood disorders with psychosis were grouped into five higher-order groups. 1,133 records were sampled for chart review using the full EHR. PPVs (the probability of chart-confirmed psychosis given ICD psychosis codes) were calculated across multiple treatment settings. Study Results: PPVs across all diagnostic groups and hospital systems exceeded 70%: Massachusetts General Brigham 0.72 [95% CI 0.68-0.77], Boston Children's Hospital 0.80 [0.75-0.84], and Boston Medical Center 0.83 [0.79-0.86]. Schizoaffective disorder PPVs were consistently the highest across sites (0.80-0.92) and major depressive disorder with psychosis were the most variable (0.57-0.79). To determine if the first documented code captured first-episode psychosis (FEP), we excluded cases with prior chart evidence of a diagnosis of or treatment for a psychotic illness, yielding substantially lower PPVs (0.08-0.62). Conclusions: We found that the first documented psychosis diagnostic code accurately captured true episodes of psychosis but was a poor index of FEP. These data have important implications for the development of risk prediction models designed to predict or detect undiagnosed psychosis.

Burden Experienced by Primary Caregivers of Children With Psychotic Disorders and at Clinical High Risk for Psychosis.

BACKGROUND: Despite the existing research exploring caregiver burden in adult psychosis, few studies have examined the experience of providing care to children diagnosed with psychotic disorders (PDs) and those identified as having clinical high risk for psychosis (CHR-P). OBJECTIVE: This study measured the level of burden in caregivers of children with PD and CHR-P and examined associated risk factors, including social support, caregiver-child relationship, severity of illness, and frequency of psychiatric hospitalizations. METHODS: A total of 56 caregivers completed validated measures and provided demographic information. Measures included the Zarit Burden Interview, the Multidimensional Scale of Perceived Social Support, the Behavior Assessment System for Children, Third Edition, Parenting Relationship Questionnaire-Child and Adolescent Form (BASC-3 PRQ-CA), and the Clinical Global Impression-Severity scale. RESULTS: The majority of caregivers were women (86%), mothers (84%), White (63%), married (66%), working full-time (50%), college-educated (79%), and whose mean age was 45.7 years (SD = 8.09). Nearly half of the caregivers (45%) reported a high level of caregiver burden, 39% rated their burden in the mild to moderate range, and 16% reported little to no burden. There was no significant difference in mean burden between PD and CHR-P groups. Higher caregiver burden was associated with lower levels of social support (r = -.408, p = .002), lower levels of parenting confidence (r = -.514, p < .001), higher levels of relational frustration (r = .612, p < .001), and higher severity of illness (r = .316 p = .025). CONCLUSIONS: These findings underscore the critical unmet need for support for caregivers of children with PD and CHR-P. Applications to clinical practice are discussed.

Poa annua: An annual species?

As the Latin name annua implies, the species Poa annua L. is thought to have an annual life cycle. Yet, there are many reports in literature of P. annua persisting as a perennial. Considering that P. annua senescence patterns do not align with other true annual species, we hypothesized that P. annua is similar to other perennial, C3 turfgrass species that are subject to a confluence of environmental factors that can cause mortality. Four experiments were conducted in Knoxville, TN with the objective of determining environmental factors lethal to P. annua. A field monitoring study assessed 100 P. annua plants across ten grassland micro-environments from May to October 2020. Forty plants survived the summer and confirmed the existence of perennial P. annua ecotypes. Analysis of environmental factors at the time of plant death indicated soil moisture, soil temperature, and pathogenic infection were associated with mortality. A series of glasshouse or field experiments were conducted to investigate the effects of each factor on P. annua mortality. Soil moisture and soil temperature were not lethal to P. annua in the glasshouse, except under extreme conditions not typical in the field. A field study assessed mortality of plants from pathogenic infection and indicated that P. annua plants treated with fungicide throughout the summer survived year-round, whereas plants not receiving fungicide applications senesced. These findings support our hypothesis that P. annua is of a perennial life cycle, which can be influenced by environmental conditions. We suggest that the name P. annua is likely a misnomer based on its modern interpretation.

Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder.

OBJECTIVE: Copy number variants (CNVs) are strongly associated with neurodevelopmental and psychotic disorders. Early-onset psychosis (EOP), where symptoms appear before 18 years of age, is thought to be more strongly influenced by genetic factors than adult-onset psychotic disorders. However, the prevalence and effect of CNVs in EOP is unclear. METHODS: The authors documented the prevalence of recurrent CNVs and the functional impact of deletions and duplications genome-wide in 137 children and adolescents with EOP compared with 5,540 individuals with autism spectrum disorder (ASD) and 16,504 population control subjects. Specifically, the frequency of 47 recurrent CNVs previously associated with neurodevelopmental and neuropsychiatric illnesses in each cohort were compared. Next, CNV risk scores (CRSs), indices reflecting the dosage sensitivity for any gene across the genome that is encapsulated in a deletion or duplication separately, were compared between groups. RESULTS: The prevalence of recurrent CNVs was significantly higher in the EOP group than in the ASD (odds ratio=2.30) and control (odds ratio=5.06) groups. However, the difference between the EOP and ASD groups was attenuated when EOP participants with co-occurring ASD were excluded. CRS was significantly higher in the EOP group compared with the control group for both deletions (odds ratio=1.30) and duplications (odds ratio=1.09). In contrast, the EOP and ASD groups did not differ significantly in terms of CRS. CONCLUSIONS: Given the high frequency of recurrent CNVs in the EOP group and comparable CRSs in the EOP and ASD groups, the findings suggest that all children and adolescents with a psychotic diagnosis should undergo genetic screening, as is recommended in ASD.

Associations between Early Psychosocial Deprivation, Cognitive and Psychiatric Morbidity, and Risk-taking Behavior in Adolescence.

OBJECTIVE: Early psychosocial deprivation increases the risk of later cognitive and psychiatric problems, but not all deprived children show these difficulties. Here, we examine the extent to which psychosocial deprivation increases the risk of later cognitive and psychiatric difficulties and the downstream consequences of this for risk-taking behavior in adolescence. METHOD: Children abandoned to institutions early in life were randomly assigned to care-as-usual or a foster care intervention during infancy. A separate group of never-institutionalized children was recruited as a comparison sample. The current follow-up study included 165 children (51% female), 113 with a history of institutionalization and 52 with no such history. At age 12, caregivers reported on children's psychiatric difficulties, and their IQ was assessed by standardized testing. At 16 years, risk-taking behavior was assessed from youth self-reports. RESULTS: Latent profile analysis revealed three subgroups of children with varying levels of cognitive and psychiatric difficulties: Low-Morbidity (n = 104, 62.7%), Medium-Morbidity (n = 46, 27.9%), and High-Morbidity (n = 15, 9.4%). Nearly half of the institutionalized children belonged to the High- or Medium-Morbidity subgroups; and institutionally-reared children were significantly more likely to belong to one of these profiles than never-institutionalized children. Compared to the Low-Morbidity subgroup, membership in the Medium-Morbidity profile was associated with higher levels of risk-taking behavior at age 16 years. CONCLUSIONS: Children who experience psychosocial deprivation are considerably more likely to present with elevated cognitive and psychiatric difficulties in early adolescence and, for some children, this elevation is linked to heightened risk-taking behavior in later adolescence.

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.

Measuring Individual Differences in Cognitive, Affective, and Spontaneous Theory of Mind Among School-Aged Children with Autism Spectrum Disorder.

The present study examined individual differences in theory of mind (ToM) among a group of 60 children (7-11 years-old) with autism spectrum disorder (ASD) and average intelligence. Using open-ended and structured tasks to measure affective ToM, cognitive ToM, and spontaneous social attribution, we explored the nature of ToM and assessed whether ToM predicts the phenotypic heterogeneity in ASD through structural equation modeling. Affective ToM uniquely predicted social symptom severity, whereas no ToM types predicted parent reported social functioning. Our findings suggest that differentiating among theoretical components is crucial for future ToM research in ASD, and ToM challenges related to reasoning about others' emotions may be particularly useful in distinguishing children with worse social symptoms of ASD.

De novo ATP1A3 and compound heterozygous NLRP3 mutations in a child with autism spectrum disorder, episodic fatigue and somnolence, and muckle-wells syndrome.

Complex phenotypes may represent novel syndromes that are the composite interaction of several genetic and environmental factors. We describe an 9-year old male with high functioning autism spectrum disorder and Muckle-Wells syndrome who at age 5  years of age manifested perseverations that interfered with his functioning at home and at school. After age 6, he developed intermittent episodes of fatigue and somnolence lasting from hours to weeks that evolved over the course of months to more chronic hypersomnia. Whole exome sequencing showed three mutations in genes potentially involved in his clinical phenotype. The patient has a predicted pathogenic de novo heterozygous p.Ala681Thr mutation in the ATP1A3 gene (chr19:42480621C>T, GRCh37/hg19). Mutations in this gene are known to cause Alternating Hemiplegia of Childhood, Rapid Onset Dystonia Parkinsonism, and CAPOS syndrome, sometimes accompanied by autistic features. The patient also has compound heterozygosity for p.Arg490Lys/p.Val200Met mutations in the NLRP3 gene (chr1:247588214G>A and chr1:247587343G>A, respectively). NLRP3 mutations are associated in an autosomal dominant manner with clinically overlapping auto-inflammatory conditions including Muckle-Wells syndrome. The p.Arg490Lys is a known pathogenic mutation inherited from the patient's father. The p.Val200Met mutation, inherited from his mother, is a variant of unknown significance (VUS). Whether the de novoATP1A3mutation is responsible for or plays a role in the patient's episodes of fatigue and somnolence remains to be determined. The unprecedented combination of two NLRP3 mutations may be responsible for other aspects of his complex phenotype.

Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

Examination of aggression and self-injury in children with autism spectrum disorders and serious behavioral problems.

This study identified subtypes of aggression in a sample of 206 children with autism spectrum disorder (ASD) who participated in 2 risperidone trials. The narratives were derived from a parent interview about each child's 2 most pressing problems. Five subtypes of aggression emerged: hot aggression only, cold aggression only, self-injurious behavior (SIB) only, aggression and SIB, and nonaggressive. All groups showed a high rate of positive response to risperidone with no differences across subtypes. These study findings extend understanding of aggression in ASD and may be useful to guide further study on biological mechanisms and individualized treatment in ASD.

Psychobiology of purging disorder: reduction in circulating leptin levels in purging disorder in comparison with controls.

OBJECTIVE: Purging disorder (PD), a recently recognized eating disorder syndrome, is differentiated from bulimia nervosa (BN) based on the absence of objectively large binge episodes. BN has been associated with low serum leptin levels. This study examined whether PD is also characterized by low serum leptin. METHOD: Participants included women with PD (n = 20) or BN (n = 37), and non-eating disorder controls (n = 33). Blood samples for measurement of leptin and total ghrelin were obtained after overnight fast. RESULTS: In comparison with control values, leptin levels were significantly decreased in PD (p < .01), as well as in BN (p < .02). Plasma ghrelin levels did not differ significantly across groups. DISCUSSION: These results provide the first evidence that PD is associated with alteration in a neurobiological pathway influencing eating patterns and body weight. Further research is needed to assess whether low leptin levels in PD and BN are associated with restrained eating and weight suppression.