title: The utility of P300 as a schizophrenia endophenotype and predictive biomarker: clinical and socio-demographic modulators in COGS-2.
abstract: Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test-retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: turetsky@upenn.edu.
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Erich M
authors.initials: EM
authors.lastname: Dress
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA; James J. Peters VA Medical Center, New York, NY, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA; James J. Peters VA Medical Center, New York, NY, USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA.
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, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Center for Behavioral Genomics and Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA; Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA, USA.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC), VA San Diego Healthcare System, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Light
mesh_terms: D000328:Adult; D001741:Black or African American; D001307:Auditory Perception / Q000502:physiology*; D015415:Biomarkers; D001921:Brain / Q000503:physiopathology*; D004569:Electroencephalography; D058068:Endophenotypes; D018913:Event-Related Potentials, P300; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D062706:Prodromal Symptoms; D011379:Prognosis; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D012907:Smoking / Q000503:physiopathology / Q000523:psychology; D012959:Socioeconomic Factors; D019966:Substance-Related Disorders / Q000150:complications / Q000503:physiopathology / Q000523:psychology
chemical_list: D015415:Biomarkers
keywords: Biomarker; Endophenotype; Event-related potential; P300; Schizophrenia