title: Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study.
abstract: Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially.
authors.affiliation: VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Millard
authors.affiliation: VISN-20 Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Shofer
authors.affiliation: VISN-22 Mental Illness Research, Education, and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Braff
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Cadenhead
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; VA Greater Los Angeles Health Care 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, San Diego, 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
authors.initials: R
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ruben
authors.initials: R
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: VISN-22 Mental Illness Research, Education, and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Nuechterlein
authors.affiliation: Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Harvard Medical School Department of Psychiatry, Boston, MA, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA; VISN-3 Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, New York, NY, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Siever
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA; VISN-3 Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, New York, NY, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Silverman
authors.affiliation: Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Harvard Medical School Department of Psychiatry, Boston, MA, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Stone
authors.affiliation: VISN-22 Mental Illness Research, Education, and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; VA Greater Los Angeles Health Care System, Los Angeles, CA, USA; Department of Biostatistics, Fielding School of Public Health at University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry, University of California, San Diego, San Diego, CA, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Turetsky
authors.affiliation: VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Radant
authors.affiliation: VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address: dwt1@uw.edu.
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058068:Endophenotypes; D005190:Family; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009483:Neuropsychological Tests; D012372:ROC Curve; D012559:Schizophrenia / Q000145:classification / Q000235:genetics*; D012565:Schizophrenic Psychology; D055815:Young Adult
keywords: Accuracy; Endophenotype; Logistic regression; Multiple imputation; ROC curve; Random forest; Schizophrenia; Sensitivity; Specificity