Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

Paolo Fusar-Poli; ENIGMA Clinical High Risk for Psychosis Working Group

doi:10.1001/jamapsychiatry.2023.3850

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

Paolo Fusar-Poli
, ENIGMA Clinical High Risk for Psychosis Working Group

Icahn School of Medicine at Mount Sinai
UBC University of British Columbia
Diakonhjemmet Hospital
University of Melbourne
University of Oslo
Boston Children's Hospital
University of Oviedo
Seoul National University
Columbia University
NICM Health Research Institute, School of Science and Health, University of Western Sydney, Australia; Division of Psychology and Mental Health, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom; Center for Youth Mental Health, University of Melbourne, Melbourne, Australia; Department of Public Health Sciences, Melbourne, Australia.
University of Oxford
University of Copenhagen
Rush University Medical Center
LVR-Hospital Cologne
USC University of Southern California
Heidelberg University
The University of Tokyo
Toho University School of Medicine
University of Bern
Copenhagen University Hospital
University of Edinburgh
Mental Health Research Center
Institute of Mental Health
Department of Clinical, Neuro- and Developmental Psychology, Amsterdam Public Health Research Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
The University of Western Australia
Department of Psychiatry, the Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
University of California
McGill University
Tokyo Metropolitan Matsuzawa Hospital
Vestre Viken Hospital Trust
Hospital Fray Bernardino Álvarez
Magnetic Resonance Imaging Core Facility

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

18 Downloads (Pure)

Abstract

IMPORTANCE: The 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.

OBJECTIVE: To 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 PARTICIPANTS: This 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 MEASURES: For 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 < -1.96) or supranormal (z > 1.96) scores.

RESULTS: Among 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 [<11.42%]) and similar to that of healthy individuals (<115 individuals [<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 RELEVANCE: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Original language	English
Pages (from-to)	77-88
Number of pages	12
Journal	JAMA Psychiatry
Volume	81
Issue number	1
Early online date	11 Oct 2023
DOIs	https://doi.org/10.1001/jamapsychiatry.2023.3850
Publication status	Published - 1 Jan 2024

Keywords

Humans
Male
Young Adult
Adult
Female
Case-Control Studies
Psychotic Disorders/diagnostic imaging
Brain/diagnostic imaging
Neuroimaging
Cognition
Prodromal Symptoms

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Cite this

@article{ab926965c835462f972c71a64dfa3003,

title = "Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis",

abstract = "IMPORTANCE: The 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.OBJECTIVE: To 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 PARTICIPANTS: This 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 MEASURES: For 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 < -1.96) or supranormal (z > 1.96) scores.RESULTS: Among 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 [<11.42\%]) and similar to that of healthy individuals (<115 individuals [<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 RELEVANCE: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.",

keywords = "Humans, Male, Young Adult, Adult, Female, Case-Control Studies, Psychotic Disorders/diagnostic imaging, Brain/diagnostic imaging, Neuroimaging, Cognition, Prodromal Symptoms",

author = "Haas, \{Shalaila S\} and Ruiyang Ge and Ingrid Agartz and Amminger, \{G Paul\} and Andreassen, \{Ole A\} and Peter Bachman and Inmaculada Baeza and Sunah Choi and Tiziano Colibazzi and Cropley, \{Vanessa L\} and \{de la Fuente-Sandoval\}, Camilo and Ebdrup, \{Bj{\o}rn H\} and Adriana Fortea and Paolo Fusar-Poli and Glenth{\o}j, \{Birte Yding\} and Glenth{\o}j, \{Louise Birkedal\} and Haut, \{Kristen M\} and Hayes, \{Rebecca A\} and Karsten Heekeren and Hooker, \{Christine I\} and Hwang, \{Wu Jeong\} and Neda Jahanshad and Michael Kaess and Kiyoto Kasai and Naoyuki Katagiri and Minah Kim and Jochen Kindler and Shinsuke Koike and Kristensen, \{Tina D\} and Kwon, \{Jun Soo\} and Lawrie, \{Stephen M\} and Irina Lebedeva and Jimmy Lee and Lemmers-Jansen, \{Imke L J\} and Ashleigh Lin and Xiaoqian Ma and Mathalon, \{Daniel H\} and Philip McGuire and Chantal Michel and Romina Mizrahi and Masafumi Mizuno and Paul M{\o}ller and Ricardo Mora-Dur{\'a}n and Barnaby Nelson and Takahiro Nemoto and Merete Nordentoft and Dorte Nordholm and Omelchenko, \{Maria A\} and Christos Pantelis and Pariente, \{Jose C\} and \{ENIGMA Clinical High Risk for Psychosis Working Group\}",

year = "2024",

month = jan,

day = "1",

doi = "10.1001/jamapsychiatry.2023.3850",

language = "English",

volume = "81",

pages = "77--88",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "1",

}

TY - JOUR

T1 - Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

AU - Haas, Shalaila S

AU - Ge, Ruiyang

AU - Agartz, Ingrid

AU - Amminger, G Paul

AU - Andreassen, Ole A

AU - Bachman, Peter

AU - Baeza, Inmaculada

AU - Choi, Sunah

AU - Colibazzi, Tiziano

AU - Cropley, Vanessa L

AU - de la Fuente-Sandoval, Camilo

AU - Ebdrup, Bjørn H

AU - Fortea, Adriana

AU - Fusar-Poli, Paolo

AU - Glenthøj, Birte Yding

AU - Glenthøj, Louise Birkedal

AU - Haut, Kristen M

AU - Hayes, Rebecca A

AU - Heekeren, Karsten

AU - Hooker, Christine I

AU - Hwang, Wu Jeong

AU - Jahanshad, Neda

AU - Kaess, Michael

AU - Kasai, Kiyoto

AU - Katagiri, Naoyuki

AU - Kim, Minah

AU - Kindler, Jochen

AU - Koike, Shinsuke

AU - Kristensen, Tina D

AU - Kwon, Jun Soo

AU - Lawrie, Stephen M

AU - Lebedeva, Irina

AU - Lee, Jimmy

AU - Lemmers-Jansen, Imke L J

AU - Lin, Ashleigh

AU - Ma, Xiaoqian

AU - Mathalon, Daniel H

AU - McGuire, Philip

AU - Michel, Chantal

AU - Mizrahi, Romina

AU - Mizuno, Masafumi

AU - Møller, Paul

AU - Mora-Durán, Ricardo

AU - Nelson, Barnaby

AU - Nemoto, Takahiro

AU - Nordentoft, Merete

AU - Nordholm, Dorte

AU - Omelchenko, Maria A

AU - Pantelis, Christos

AU - Pariente, Jose C

AU - ENIGMA Clinical High Risk for Psychosis Working Group

PY - 2024/1/1

Y1 - 2024/1/1

N2 - IMPORTANCE: The 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.OBJECTIVE: To 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 PARTICIPANTS: This 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 MEASURES: For 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 < -1.96) or supranormal (z > 1.96) scores.RESULTS: Among 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 [<11.42%]) and similar to that of healthy individuals (<115 individuals [<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 RELEVANCE: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

AB - IMPORTANCE: The 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.OBJECTIVE: To 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 PARTICIPANTS: This 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 MEASURES: For 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 < -1.96) or supranormal (z > 1.96) scores.RESULTS: Among 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 [<11.42%]) and similar to that of healthy individuals (<115 individuals [<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 RELEVANCE: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

KW - Humans

KW - Male

KW - Young Adult

KW - Adult

KW - Female

KW - Case-Control Studies

KW - Psychotic Disorders/diagnostic imaging

KW - Brain/diagnostic imaging

KW - Neuroimaging

KW - Cognition

KW - Prodromal Symptoms

U2 - 10.1001/jamapsychiatry.2023.3850

DO - 10.1001/jamapsychiatry.2023.3850

M3 - Article

C2 - 37819650

SN - 2168-622X

VL - 81

SP - 77

EP - 88

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 1

ER -

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

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