European Child and Adolescent Psychiatry

Predictors of Schizophrenia Spectrum Disorders in Early-onset First Episodes of Psychosis: A Support Vector Machine Model

European Child and Adolescent Psychiatry

Laura Pina-Camacho, Juan Garcia-Prieto, Mara Parellada, Josefina Castro-Fornieles, Ana M Gonzalez-Pinto, Igor Bombin, Montserrat Graell, Beatriz Paya, Marta Rapado-Castro, Joost Janssen, Inmaculada Baeza, Francisco Del Pozo, Manuel Desco, Celso Arango

L. Pina-Camacho

Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón. School of Medicine, Universidad Complutense, IiSGM, CIBERSAM. Ibiza 43, 28009 Madrid, Spain

Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King’s College London, De Crespigny Park, SE5 8AF, London, United Kingdom

E-mail address:

Online Resource 1

Clinical and functional assessments

At baseline, for patients and healthy controls, clinical and functional assessments were performed by experienced psychiatrists. Information was gathered from interviews with subjects, parents and other relevant informants and from medical records. Assessments included recording of demographic data (age, sex, ethnicity, socioeconomic status by means of the Hollingshead-Redlich scale [1], parent and child years of education), developmental and educational history, personal medical and psychiatric history, family psychiatric history, past and current substance misuse, past and current psychopharmacological treatment, first psychotic symptoms and duration of illness defined as the time elapsed between the first positive symptom (delusions, hallucinations or disorganization) recalled and the baseline assessment.

Clinical and functional scales were also administered by experienced psychiatrists at each site, including the Lewis–Murray scale for obstetric complications [2], the family environment scale (FES) [3], the premorbid adjustment scale (PAS) [4], the validated Spanish version of the positive and negative symptom scale (PANSS) [5], the Hamilton depression sating scale (HDRS) [6], the Young mania rating scale (YMRS) [7], the scale to assess unawareness of mental disorder (SUMD), abbreviated version [8], the clinical global impression scale-severity (CGI-S) [9], the children's global assessment scale (CGAS) [10], the Strauss–Carpenter outcomes scale (SCOS) [11], the strengths and difficulties questionnaire (SDQ) [12], the parent–adolescent communication inventory (PACI) [13] and the World Health Organization disability assessment schedule (WHO-DAS), short version [14]. A physical examination was also performed by trained nurses at each site. Anthropometric data (weight, height and body mass index) were recorded.

Intraclass correlation coefficients for PANSS inter-rater reliability were higher than 0.8. A complete description of the clinical and functional scales has been provided elsewhere [15].

For the purposes of this study, ratings of every item on the above-mentioned scales, subscores (where appropriate, e.g. PANSS positive, negative and general subscores) and total scores (where appropriate) were included in the model.

Neuropsychological assessment

At baseline, a comprehensive neuropsychological assessment was performed by 6 trained and experienced psychologists. The vocabulary and block design subtests of the Wechsler intelligence scale for children-revised (WISC-R) or the Wechsler adult intelligence scale, 3rd edition (WAIS-III) were used to estimate the intelligence quotient (IQ) of those younger than 16 years or 16 years of age and older, respectively. A neuropsychological battery including the trail making test, parts A and B (TMT-A and TMT-B), continuous performance test-II (CPT), Stroop test, Spanish version of the California verbal learning test (TAVEC), FAS verbal fluency test, controlled oral word association test (COWAT), and the Wisconsin card sorting test (WCST) was administered to patients and controls. This battery was designed to assess five cognitive domains by combining selected individual measures from different tests: attention (by combining WAIS-III/WISC-R digits forward, time to complete TMT-A, number of correct items Stroop 1 words and number of correct items Stroop 2 colors), speed of processing (by combining time to complete TMT-A, number of correct items Stroop 1 words, number of correct items Stroop 2 colors, and average number of words on the FAS),verbal learning and memory (by combining TAVEC total learning, short term free recall, long term free recall and discrimination),working memory (by combining WAIS-III/WISC-R digits backwards and number-letter sequencing) and executive functioning (by combining TMT-B – TMT-A, number of words on the FAS, number of words on the COWAT, Stroop interference score, WCST number of perseverative errors, WCST number of errors and WCST conceptual level responses). The mean summary scores (attention, speed of processing, learning and memory, working memory, and executive function) were calculated as the arithmetic means of the individual measurements that composed the specific cognitive domains. A global cognitive score was also calculated as the arithmetic mean of the five cognitive domains.

The neurological evaluation scale (NES) [16] was also administered by the same trained and experienced psychologists.

For all subjects, raw scores were transformed to z-scores (mean 0; SD 1) based on the performance of the control group at baseline. Z scores were truncated at ± 4, to avoid outlying values. Inter-rater reliability (intraclass correlation coefficient) ranged from 0.80 to 0.99 in all administered scales.A complete description of the neuropsychological tests has been provided elsewhere [17].

For the purposes of this study, raw scores and z-scores of every single test variable, raw and z-subscores (where appropriate, e.g. NES) and raw and z- total or summary scores (where appropriate) were included in the model.

Neuroimaging assessment

An anatomical brain magnetic resonance imaging (MRI) scan was acquired within 3 months after the baseline assessment. Five different 1.5T scanners contributed data to the study (2 Siemens Symphony scanners, 2 General Electric Signa scanners and 1 Philips ACS Gyroscan). The acquisition protocol consisted of a T1-weighted 3D gradient-echo sequence with 1.5 mm slice thickness (in-plane voxel size 0.98 x 0.98 mm2) and a T2-weighted turbo spin-echo sequence with 3.5 mm slice thickness (in-plane voxel size 0.98 x 0.98 mm2). To minimize the effect of the multicenter design, patients and controls were age- and sex- matched within each of the contributing sites.

Data were processed at only one site. First, the segmentation of the brain tissues was performed using a semi-automated segmentation of the brain based on the Talairach proportional grid system [18-19] and then volumes were quantified with a locally devised validated methodology [20]. The regions of interest (ROIs) included in the analysis included the frontal lobe, parietal lobe, temporal lobe (whole temporal, mesial and external subregions), occipital lobe, orbital cortex, dorsolateral prefrontal cortex, subcortical regions (including caudate, putamen, thalamus, internal capsule and globus pallidus) and hippocampus. For each ROI, raw volumes and volume percentages for each hemisphere and for gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) (within each ROI) were obtained.Whole-brain GM, WM and CSF were also measured. Intracranial volume (ICV) was measured by adding the total GM, WM and CSF volumes, including the cerebellum.

A previous study about compatibility among the scanners showed that the intersite coefficient of variation ranged from 1.8% to 5.2%, respectively, for GM and CSF volumes, whereas estimations of WM volume and occipital lobe volumes were more prone to site-related errors [21]. Full details about the acquisition parameters and procedures at each site, the comparability between machines for this study, and data processing have been published elsewhere [21-23].

Biochemical determinations

At baseline, for both patients and controls, blood samples were collected and processed at each site following standard procedures. Blood cells and plasma were immediately frozen and stored at -80°C until analysis. All samples were analyzed in a single batch by an experienced and trained biochemist. Primary enzymatic antioxidant defense (cellular glutathione peroxidase, catalase and superoxide dismutase activities), total antioxidant status (TAS), lipid peroxidation and levels of glutathione in plasma were determined by standardized assays. A complete description of the oxidative stress determinations and of the standardized assays has been provided elsewhere [24].

References

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