Dynamic Prediction of Outcomes for Youth at Clinical High Risk for Psychosis: A Joint Modeling Approach.

Importance: Leveraging the dynamic nature of clinical variables in the clinical high risk for psychosis (CHR-P) population has the potential to significantly improve the performance of outcome prediction models. Objective: To improve performance of prediction models and elucidate dynamic clinical profiles using joint modeling to predict conversion to psychosis and symptom remission. Design, Setting, and Participants: Data were collected as part of the third wave of the North American Prodrome Longitudinal Study (NAPLS 3), which is a 9-site prospective longitudinal study. Participants were individuals aged 12 to 30 years who met criteria for a psychosis-risk syndrome. Clinical, neurocognitive, and demographic variables were collected at baseline and at multiple follow-up visits, beginning at 2 months and up to 24 months. An initial feature selection process identified longitudinal clinical variables that showed differential change for each outcome group across 2 months. With these variables, a joint modeling framework was used to estimate the likelihood of eventual outcomes. Models were developed and tested in a 10-fold cross-validation framework. Clinical data were collected between February 2015 and November 2018, and data were analyzed from February 2022 to December 2023. Main Outcomes and Measures: Prediction models were built to predict conversion to psychosis and symptom remission. Participants met criteria for conversion if their positive symptoms reached the fully psychotic range and for symptom remission if they were subprodromal on the Scale of Psychosis-Risk Symptoms for a duration of 6 months or more. Results: Of 488 included NAPLS 3 participants, 232 (47.5%) were female, and the mean (SD) age was 18.2 (3.4) years. Joint models achieved a high level of accuracy in predicting conversion (balanced accuracy [BAC], 0.91) and remission (BAC, 0.99) compared with baseline models (conversion: BAC, 0.65; remission: BAC, 0.60). Clinical variables that showed differential change between outcome groups across a 2-month span, including measures of symptom severity and aspects of functioning, were also identified. Further, intra-individual risks for each outcome were more negatively correlated when using joint models (r = -0.92; P < .001) compared with baseline models (r = -0.50; P < .001). Conclusions and Relevance: In this study, joint models significantly outperformed baseline models in predicting both conversion and remission, demonstrating that monitoring short-term clinical change may help to parse heterogeneous dynamic clinical trajectories in a CHR-P population. These findings could inform additional study of targeted treatment selection and could move the field closer to clinical implementation of prediction models.

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.