Development and temporal validation of a clinical prediction model of transition to psychosis in individuals at ultra-high risk in the UHR 1000+ cohort.

The concept of ultra-high risk for psychosis (UHR) has been at the forefront of psychiatric research for several decades, with the ultimate goal of preventing the onset of psychotic disorder in high-risk individuals. Orygen (Melbourne, Australia) has led a range of observational and intervention studies in this clinical population. These datasets have now been integrated into the UHR 1000+ cohort, consisting of a sample of 1,245 UHR individuals with a follow-up period ranging from 1 to 16.7 years. This paper describes the cohort, presents a clinical prediction model of transition to psychosis in this cohort, and examines how predictive performance is affected by changes in UHR samples over time. We analyzed transition to psychosis using a Cox proportional hazards model. Clinical predictors for transition to psychosis were investigated in the entire cohort using multiple imputation and Rubin's rule. To assess performance drift over time, data from 1995-2016 were used for initial model fitting, and models were subsequently validated on data from 2017-2020. Over the follow-up period, 220 cases (17.7%) developed a psychotic disorder. Pooled hazard ratio (HR) estimates showed that the Comprehensive Assessment of At-Risk Mental States (CAARMS) Disorganized Speech subscale severity score (HR=1.12, 95% CI: 1.02-1.24, p=0.024), the CAARMS Unusual Thought Content subscale severity score (HR=1.13, 95% CI: 1.03-1.24, p=0.009), the Scale for the Assessment of Negative Symptoms (SANS) total score (HR=1.02, 95% CI: 1.00-1.03, p=0.022), the Social and Occupational Functioning Assessment Scale (SOFAS) score (HR=0.98, 95% CI: 0.97-1.00, p=0.036), and time between onset of symptoms and entry to UHR service (log transformed) (HR=1.10, 95% CI: 1.02-1.19, p=0.013) were predictive of transition to psychosis. UHR individuals who met the brief limited intermittent psychotic symptoms (BLIPS) criteria had a higher probability of transitioning to psychosis than those who met the attenuated psychotic symptoms (APS) criteria (HR=0.48, 95% CI: 0.32-0.73, p=0.001) and those who met the Trait risk criteria (a first-degree relative with a psychotic disorder or a schizotypal personality disorder plus a significant decrease in functioning during the previous year) (HR=0.43, 95% CI: 0.22-0.83, p=0.013). Models based on data from 1995-2016 displayed good calibration at initial model fitting, but showed a drift of 20.2-35.4% in calibration when validated on data from 2017-2020. Large-scale longitudinal data such as those from the UHR 1000+ cohort are required to develop accurate psychosis prediction models. It is critical to assess existing and future risk calculators for temporal drift, that may reduce their utility in clinical practice over time.

Retrospective Examination of Peripubertal Return for Patients of Western Australia's Gender Diversity Service.

Purpose: Children far in advance of pubertal development may be deferred from further assessment for gender-affirming medical treatment until nearer puberty. It is vital that returning peripubertal patients are seen promptly to ensure time-sensitive assessment and provision of puberty suppression treatment where appropriate. This study investigates (1) how many referrals to the Child and Adolescent Health Service Gender Diversity Service at Perth Children's Hospital are deferred due to prepubertal status; and (2) how many deferred patients return peripubertally. Methods: A retrospective review of all closed referrals to the service was conducted to determine the frequency of prepubertal deferral and peripubertal re-referral. Results: Of 995 referrals received (2014 to 2020), 552 were closed. The reason for closure was determined for 548 referrals (99.3%). Prepubertal status was the second-most frequent reason for closure, and the most frequent for birth-registered males. Twenty-five percent of all deferred prepubertal patients returned peripubertally, before audit closure. A greater return frequency (55.6%) was estimated for those older than 13 years at audit closure. Conclusion: High rates of prepubertal referral indicate the importance of pediatric gender services in providing information, advice, and reassurance to concerned families. With increasing service demand, high rates of return peripubertally have implications for service planning to ensure that returning peripubertal patients are seen promptly for time-sensitive care. Frequency of peripubertal re-referral cannot, however, speak to the stability of trans identity or gender incongruence from childhood to adolescence. Clinics advising prepubertal deferral must proactively plan to ensure that sufficient clinical resources are reserved for this purpose.

Reidentification With Birth-Registered Sex in a Western Australian Pediatric Gender Clinic Cohort.

Importance: Some young people who identify as transgender and seek gender-affirming medical care subsequently reidentify with their sex registered at birth. Evidence regarding the frequency and characteristics of this experience is lacking. Objective: To determine the frequency of reidentification and explore associated characteristics in a pediatric gender clinic setting. Design, Setting, and Participants: This retrospective cohort study examined all referrals to the Child and Adolescent Health Service Gender Diversity Service at Perth Children's Hospital between January 1, 2014, and December 31, 2020. The Gender Diversity Service is the sole statewide specialist service in Western Australia that provides children and adolescents up to age 18 years with multidisciplinary assessment, information, support, and gender-affirming medical care. All closed referrals for this study were audited between May 1, 2021, and August 8, 2022. Exposure: Reidentification with birth-registered sex. Main Outcomes and Measures: The number of referrals closed due to reported reidentification with birth-registered sex was determined, as well as descriptives and frequencies of patient demographics (age, birth-registered sex), informant source, International Statistical Classification of Diseases, Tenth Revision gender-related diagnoses, pubertal status, any gender-affirming medical treatment received, and whether subsequent re-referrals were received. Results: Of 552 closed referrals during the study period, a reason for closure could be determined for 548 patients, including 211 birth-registered males (mean [SD] age, 13.88 [2.00] years) and 337 birth-registered females (mean [SD] age, 15.81 [2.22] years). Patients who reidentified with their birth-registered sex comprised 5.3% (29 of 548; 95% CI, 3.6%-7.5%) of all referral closures. Except for 2 patients, reidentification occurred before or during early stages of assessment (93.1%; 95% CI, 77.2%-99.2%). Two patients who reidentified with their birth-registered sex did so following initiation of puberty suppression or gender-affirming hormone treatment (1.0% of 196 patients who initiated any gender-affirming medical treatment; 95% CI, 0.1%-3.6%). Conclusions and Relevance: These findings from a pediatric gender clinic audit indicate that a small proportion of patients, and a very small proportion of those who initiated medical gender-affirming treatment, reidentified with their birth-registered sex during the study period. Longitudinal follow-up studies, including qualitative self-report, are required to understand different pathways of gender identity experience.

Combining Clinical With Cognitive or Magnetic Resonance Imaging Data for Predicting Transition to Psychosis in Ultra High-Risk Patients: Data From the PACE 400 Cohort.

BACKGROUND: Multimodal modeling that combines biological and clinical data shows promise in predicting transition to psychosis in individuals who are at ultra-high risk. Individuals who transition to psychosis are known to have deficits at baseline in cognitive function and reductions in gray matter volume in multiple brain regions identified by magnetic resonance imaging. METHODS: In this study, we used Cox proportional hazards regression models to assess the additive predictive value of each modality-cognition, cortical structure information, and the neuroanatomical measure of brain age gap-to a previously developed clinical model using functioning and duration of symptoms prior to service entry as predictors in the Personal Assessment and Crisis Evaluation (PACE) 400 cohort. The PACE 400 study is a well-characterized cohort of Australian youths who were identified as ultra-high risk of transitioning to psychosis using the Comprehensive Assessment of At Risk Mental States (CAARMS) and followed for up to 18 years; it contains clinical data (from N = 416 participants), cognitive data (n = 213), and magnetic resonance imaging cortical parameters extracted using FreeSurfer (n = 231). RESULTS: The results showed that neuroimaging, brain age gap, and cognition added marginal predictive information to the previously developed clinical model (fraction of new information: neuroimaging 0%-12%, brain age gap 7%, cognition 0%-16%). CONCLUSIONS: In summary, adding a second modality to a clinical risk model predicting the onset of a psychotic disorder in the PACE 400 cohort showed little improvement in the fit of the model for long-term prediction of transition to psychosis.

Potential immunological effects of gender-affirming hormone therapy in transgender people - an unexplored area of research.

There are well-described sex-based differences in how the immune system operates. In particular, cisgender (cis) females have a more easily activated immune system; associated with an increased prevalence of autoimmune diseases and adverse events following vaccinations. Conversely, cis males have a higher threshold for immune activation, and are more prone to certain infectious diseases, such as coronavirus disease (COVID-19). Oestrogen and testosterone have immune-modulatory properties, and it is likely that these contribute to the sexual dimorphism of the immune system. There are also important immune-related genes located on the X chromosome, such as toll-like receptor (TLR) 7/8; and the mosaic bi-allelic expression of such genes may contribute to the state of immune hyperactivation in cis females. The scientific literature strongly suggests that sex-based differences in the functioning of the immune system are related to both X-linked genes and immune modulation by sex hormones. However, it is currently not clear how this impacts transgender (trans) people receiving gender-affirming hormonal therapy. Moreover, it is estimated that in Australia, at least 2.3% of adolescents identify as trans and/or gender diverse, and referrals to specialist gender-affirming care are increasing each year. Despite the improving social awareness of trans people, they remain chronically underrepresented in the scientific literature. In addition, a small number of case studies describe new onset autoimmune disorders in adult trans females following oestrogen use. However, there is currently minimal long-term research with an immunological focus on trans people. Therefore, to ensure the positive health outcomes of trans people, it is crucial that the role of sex hormones in immune modulation is investigated further.