Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis
Authors:   ENIGMA Clinical High Risk for Psychosis Working Group, Allen Paul , Baldwin Helen , Bartholomeusz Cali F , Chee Michael WL , Chen Xiaogang , Cooper Rebecca E , de Haan Lieuwe , Hamilton Holly K , He Ying , Hegelstad Wenche ten Velden , Horton Leslie E , Hubl Daniela , Klaunig Mallory J , Koppel Alex , Kwak Yoo Bin , León-Ortiz Pablo , Loewy Rachel L , McGorry Patrick , Ouyang Lijun , Rasser Paul E , Resch Franz , Schiffman Jason , Sørensen Mikkel E , Tang Jinsong , Velakoulis Dennis , Vinogradov Sophia , Yamasue Hidenori , Yuan Liu , Yung Alison R , Haas Shalaila S. , Ge Ruiyang , Agartz Ingrid , Amminger G. Paul , Andreassen Ole A. , Bachman Peter , Baeza Inmaculada , Choi Sunah , Colibazzi Tiziano , Cropley Vanessa L. , de la Fuente-Sandoval Camilo , Ebdrup Bjørn H. , Fortea Adriana , Fusar-Poli Paolo , Glenthøj Birte Yding , Glenthøj Louise Birkedal , Haut Kristen M. , Hayes Rebecca A. , Heekeren Karsten , Hooker Christine I. , Hwang Wu Jeong , Jahanshad Neda , Kaess Michael , Kasai Kiyoto , Katagiri Naoyuki , Kim Minah , Kindler Jochen , Koike Shinsuke , Kristensen Tina D. , Kwon Jun Soo , Lawrie Stephen M. , Lebedeva Irina , Lee Jimmy , Lemmers-Jansen Imke L. J. , Lin Ashleigh , Ma Xiaoqian , Mathalon Daniel H. , McGuire Philip , Michel Chantal , Mizrahi Romina , Mizuno Masafumi , Møller Paul , Mora-Durán Ricardo , Nelson Barnaby , Nemoto Takahiro , Nordentoft Merete , Nordholm Dorte , Omelchenko Maria A. , Pantelis Christos , Pariente Jose C. , Raghava Jayachandra M. , Reyes-Madrigal Francisco , Røssberg Jan I. , Rössler Wulf , Salisbury Dean F. , Sasabayashi Daiki , Schall Ulrich , Smigielski Lukasz , Sugranyes Gisela , Suzuki Michio , Takahashi Tsutomu , Tamnes Christian K. , Theodoridou Anastasia , Thomopoulos Sophia I. , Thompson Paul M. , Tomyshev Alexander S. , Uhlhaas Peter J. , Værnes Tor G. , van Amelsvoort Therese A. M. J. , van Erp Theo G. M. , Waltz James A. , Wenneberg Christina , Westlye Lars T. , Wood Stephen J. , Zhou Juan H. , Hernaus Dennis , Jalbrzikowski Maria , Kahn René S. , Corcoran Cheryl M. , Frangou Sophia 
Published: October 2023

ImportanceThe lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals.ObjectiveTo quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder.Design, Setting, and ParticipantsThis case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)–derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022.Main Outcomes and MeasuresFor each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z &amp;lt; −1.96) or supranormal (z &amp;gt; 1.96) scores.ResultsAmong 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [&amp;lt;11.42%]) and similar to that of healthy individuals (&amp;lt;115 individuals [&amp;lt;9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = −0.08; 95% CI, −0.13 to −0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate).Conclusions and RelevanceIn this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.