title: Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2.
abstract: Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, United States. Electronic address: glight@ucsd.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Thomas
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States; VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, United States.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Marlena
authors.initials: M
authors.lastname: Pela
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States; VA Puget Sound Health Care System, Seattle, WA, United States.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, United States.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Sharp
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, United States; James J. Peters VA Medical Center, New York, NY, United States.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, United States; James J. Peters VA Medical Center, New York, NY, United States.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, United States.
authors.forename: William S
authors.initials: WS
authors.lastname: Stone
authors.affiliation: Department of Biostatistics, University of California Los Angeles School of Public Health, Los Angeles, CA, United States.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States; VA Puget Sound Health Care System, Seattle, WA, United States.
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States; Center for Behavioral Genomics, and Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, United States; Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, United States.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
mesh_terms: D000161:Acoustic Stimulation; D000293:Adolescent; D000328:Adult; D000368:Aged; D001307:Auditory Perception / Q000502:physiology*; D001921:Brain / Q000503:physiopathology*; D004569:Electroencephalography; D058068:Endophenotypes; D018913:Event-Related Potentials, P300; D005072:Evoked Potentials, Auditory; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D012907:Smoking / Q000503:physiopathology; D012959:Socioeconomic Factors; D055815:Young Adult
keywords: Cognition; EEG; Function; Mismatch negativity; P300; P3a; Schizophrenia