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Clinical Indicators of Treatment-Resistant PSYCHOSISSupplementary Information TOC \t "Heading 1,3,Heading 2,1,Heading 3,2" Supplementary Methods PAGEREF _Toc416518798 \h 2Sample description PAGEREF _Toc416518799 \h 2Genotyping and quality control PAGEREF _Toc416518800 \h 3Schizophrenia polygenic risk score (PRS) PAGEREF _Toc416518801 \h 3Copy number variation (CNVs) PAGEREF _Toc416518802 \h 4Supplementary Table 1: Diagnoses of study individuals PAGEREF _Toc416518803 \h 5Supplementary Table 2: Definitions of clinical predictive variables PAGEREF _Toc416518804 \h 6Supplementary Table 3: Definitions of lifetime clinical variables PAGEREF _Toc416518805 \h 8Supplementary Table 4: Characteristics of participants with missing data PAGEREF _Toc416518806 \h 10Supplementary Table 5: Lifetime characteristics PAGEREF _Toc416518807 \h 11Supplementary Table 6: Lifetime clinical characteristics (SZ only) PAGEREF _Toc416518808 \h 12Supplementary Table 7: Clinical predictors of TRP (SZ only) PAGEREF _Toc416518809 \h 13Supplementary Table 8: Multivariate model (N=337) PAGEREF _Toc416518810 \h 14Supplementary Table 9: Schizophrenia PRS and TRP (SZ only) PAGEREF _Toc416518811 \h 15Supplementary Table 10: CNVs and TRP (SZ only) PAGEREF _Toc416518812 \h 16Supplementary Table 11: Proportion of TRP by age of onset of psychosis PAGEREF _Toc416518813 \h 17Supplementary Table 12: Predictive analysis of age of onset of psychosis PAGEREF _Toc416518814 \h 18Supplementary Table 13: Schizophrenia PRS and age of onset PAGEREF _Toc416518815 \h 19Supplementary Table 14: Schizophrenia PRS and age of onset (SZ only) PAGEREF _Toc416518816 \h 19Supplementary Figure 1: Correlation matrix of clinical predictive variables PAGEREF _Toc416518817 \h 20Supplementary Figure 2: Conditional inference forests model (SZ only) PAGEREF _Toc416518818 \h 21References PAGEREF _Toc416518819 \h 22Supplementary MethodsSample descriptionStudy individuals were from the CardiffCOGS (COGnition in Schizophrenia) sample, which has been previously describedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MeW5oYW08L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 1,2. The sample consists of a total of 1302 individuals with schizophrenia (n=767), schizoaffective disorder depressed type (n=168), schizoaffective disorder bipolar type (n=119), related psychotic disorders (n=114), and mood disorders (n=129). All patient groups were recruited as part of a single study, and all aspects of phenotyping and research diagnosis were equivalent across groups. The study was conducted from Cardiff University and participants were recruited from community, in-patient and voluntary sector mental health services from across the UK, but primarily Cardiff and South Wales. Eligibility criteria included a diagnosis of schizophrenia, psychotic disorder or bipolar disorder and aged between 16 and 65 at the time of recruitment. Participants were excluded if they had a neurological condition (including intellectual disability, dementia, or brain damage) that was likely to affect their ability to participate in the study, or if they had a current substance dependence disorder.Study individuals completed a comprehensive clinical interview based on the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) instrument ADDIN EN.CITE <EndNote><Cite><Author>Wing</Author><Year>1990</Year><RecNum>4725</RecNum><DisplayText><style face="superscript">3</style></DisplayText><record><rec-number>4725</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1518432422">4725</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wing, J. K.</author><author>Babor, T.</author><author>Brugha, T.</author><author>Burke, J.</author><author>Cooper, J. E.</author><author>Giel, R.</author><author>Jablenski, A.</author><author>Regier, D.</author><author>Sartorius, N.</author></authors></contributors><titles><title>SCAN: Schedules for Clinical-Assessment in Neuropsychiatry</title><secondary-title>Archives of General Psychiatry</secondary-title><alt-title>Arch Gen Psychiat</alt-title></titles><periodical><full-title>Archives of general psychiatry</full-title><abbr-1>Arch Gen Psychiatry</abbr-1></periodical><pages>589-593</pages><volume>47</volume><number>6</number><dates><year>1990</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0003-990x</isbn><accession-num>WOS:A1990DJ13200010</accession-num><urls><related-urls><url><Go to ISI>://WOS:A1990DJ13200010</url></related-urls></urls><language>English</language></record></Cite></EndNote>3, donated a blood sample for genetic analysis, completed the MATRICS cognitive batteryPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OdWVjaHRlcmxlaW48L0F1dGhvcj48WWVhcj4yMDA4PC9Z
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ADDIN EN.CITE.DATA 4, and consented for access to their clinical case notes. Trained psychiatrists or psychology graduates conducted these interviews, and regular inter-rater reliability was undertaken. Trained raters reviewed this interview, along with available clinical records, to complete OPCRIT ratings ADDIN EN.CITE <EndNote><Cite><Author>Mcguffin</Author><Year>1991</Year><RecNum>4724</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>4724</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1518426025">4724</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mcguffin, P.</author><author>Farmer, A.</author><author>Harvey, I.</author></authors></contributors><auth-address>Inst Psychiat,London Se5 8af,England</auth-address><titles><title>A Polydiagnostic Application of Operational Criteria in Studies of Psychotic Illness - Development and Reliability of the Opcrit System</title><secondary-title>Archives of General Psychiatry</secondary-title><alt-title>Arch Gen Psychiat</alt-title></titles><periodical><full-title>Archives of general psychiatry</full-title><abbr-1>Arch Gen Psychiatry</abbr-1></periodical><pages>764-770</pages><volume>48</volume><number>8</number><keywords><keyword>diagnostic interview</keyword><keyword>twin concordance</keyword><keyword>schizophrenia</keyword><keyword>reanalysis</keyword></keywords><dates><year>1991</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0003-990x</isbn><accession-num>WOS:A1991GA24600013</accession-num><urls><related-urls><url><Go to ISI>://WOS:A1991GA24600013</url></related-urls></urls><language>English</language></record></Cite></EndNote>5 and to determine a consensus lifetime DSM-IV and ICD-10 diagnosis22?(inter-rater reliability κ statistics: schizophrenia = 0.83, schizoaffective depressive = 0.63, schizoaffective bipolar = 0.72, bipolar disorder = 0.85).Genotyping and quality controlThe CardiffCOGS sample was genotyped on either the Illumina HumanOmniExpressExome-8 array at the Broad Institute (Massachusetts, USA) or the Illumina HumanOmniExpress-12 array at DeCode Genetics (Reykjavik, Iceland) as previously describedPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWVzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 8, removing all individuals and SNPs with coverage < 2%, the data was imputed using IMPUTE2 ADDIN EN.CITE <EndNote><Cite><Author>Howie</Author><Year>2009</Year><RecNum>4099</RecNum><DisplayText><style face="superscript">9</style></DisplayText><record><rec-number>4099</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1425913171">4099</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Howie, B. N.</author><author>Donnelly, P.</author><author>Marchini, J.</author></authors></contributors><auth-address>Department of Statistics, University of Oxford, Oxford, UK.</auth-address><titles><title>A flexible and accurate genotype imputation method for the next generation of genome-wide association studies</title><secondary-title>PLoS Genetics</secondary-title><alt-title>PLoS Genet</alt-title></titles><periodical><full-title>PLoS Genet</full-title><abbr-1>PLoS genetics</abbr-1></periodical><alt-periodical><full-title>PLoS Genet</full-title><abbr-1>PLoS genetics</abbr-1></alt-periodical><pages>e1000529</pages><volume>5</volume><number>6</number><keywords><keyword>Genetics, Population</keyword><keyword>Genome-Wide Association Study/*methods</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>Polymorphism, Single Nucleotide</keyword><keyword>Software</keyword></keywords><dates><year>2009</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1553-7404 (Electronic)
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ADDIN EN.CITE.DATA 10. Best-guess genotypes were generated from the imputed data for SNPs with imputation (INFO) score ≥ 0.9, minor allele frequency (MAF) ≥ 1%, and HWE p-value ≤ 1 x 10-10. All genetic analyses were restricted to those of European ancestry, assessed by principal component analysis, and related individuals with ? > 0.2 were identified and one member removed at random. Schizophrenia polygenic risk score (PRS)Polygenic risk scores were created based on the results from the latest large scale schizophrenia GWAS meta-analysisPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJkaW5hczwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+
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ADDIN EN.CITE.DATA 2 comprised of the Psychiatric Genomics Consortium GWAS (PGC2, excluding individuals from CardiffCOGS) ADDIN EN.CITE <EndNote><Cite><Author>Schizophrenia Working Group of the Psychiatric Genomics Consortium</Author><Year>2014</Year><RecNum>4226</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>4226</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1435143642">4226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schizophrenia Working Group of the Psychiatric Genomics Consortium,</author></authors></contributors><titles><title>Biological insights from 108 schizophrenia-associated genetic loci</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>421-7</pages><volume>511</volume><number>7510</number><keywords><keyword>Alleles</keyword><keyword>Brain/metabolism/physiology</keyword><keyword>Enhancer Elements, Genetic/genetics</keyword><keyword>*Genetic Loci</keyword><keyword>Genetic Predisposition to Disease/*genetics</keyword><keyword>*Genome-Wide Association Study</keyword><keyword>Glutamic Acid/metabolism</keyword><keyword>Humans</keyword><keyword>Immunity/genetics/physiology</keyword><keyword>Multifactorial Inheritance/genetics</keyword><keyword>Mutation/genetics</keyword><keyword>Odds Ratio</keyword><keyword>Polymorphism, Single Nucleotide/genetics</keyword><keyword>Schizophrenia/*genetics/immunology</keyword><keyword>Synaptic Transmission/genetics</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul 24</date></pub-dates></dates><isbn>1476-4687 (Electronic)
0028-0836 (Linking)</isbn><accession-num>25056061</accession-num><urls><related-urls><url> and CLOZUK2 ADDIN EN.CITE <EndNote><Cite><Author>Pardi?as</Author><Year>2016</Year><RecNum>4672</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>4672</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1471512996">4672</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pardi?as, Antonio F</author><author>Holmans, Peter</author><author>Pocklington, Andrew J</author><author>Escott-Price, Valentina</author><author>Ripke, Stephan</author><author>Carrera, Noa</author><author>Legge, Sophie E</author><author>Bishop, Sophie</author><author>Cameron, Darren</author><author>Hamshere, Marian L</author><author>Han, Jun</author><author>Hubbard, Leon</author><author>Lynham, Amy</author><author>Mantripragada, Kiran</author><author>Rees, Elliott</author><author>MacCabe, James H</author><author>McCarroll, Steven A</author><author>Baune, Bernhard T</author><author>Breen, Gerome</author><author>Byrne, Enda M</author><author>Dannlowski, Udo</author><author>Eley, Thalia C</author><author>Hayward, Caroline</author><author>Martin, Nicholas G</author><author>McIntosh, Andrew M</author><author>Plomin, Robert</author><author>Porteous, David J</author><author>Wray, Naomi R</author><author>Collier, David A</author><author>Rujescu, Dan</author><author>Kirov, George</author><author>Owen, Michael J</author><author>O'Donovan, Michael C</author><author>Walters, James T R</author></authors></contributors><titles><title>Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection</title><secondary-title>bioRxiv</secondary-title></titles><periodical><full-title>bioRxiv</full-title></periodical><dates><year>2016</year></dates><urls></urls><electronic-resource-num>10.1101/068593</electronic-resource-num></record></Cite></EndNote>12, totalling 39,915 schizophrenia cases and 64,639 controls. Risk scores were calculated following the method described by Wray et al (2014) ADDIN EN.CITE <EndNote><Cite><Author>Wray</Author><Year>2014</Year><RecNum>4719</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>4719</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1517497623">4719</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wray, N. R.</author><author>Lee, S. H.</author><author>Mehta, D.</author><author>Vinkhuyzen, A. A.</author><author>Dudbridge, F.</author><author>Middeldorp, C. M.</author></authors></contributors><auth-address>Queensland Brain Institute, The University of Queensland, St Lucia, Qld, Australia.</auth-address><titles><title>Research review: Polygenic methods and their application to psychiatric traits</title><secondary-title>Journal of Child Psychology and Psychiatry</secondary-title><alt-title>J Child Psychol Psychiatry</alt-title></titles><alt-periodical><full-title>J Child Psychol Psychiatry</full-title></alt-periodical><pages>1068-87</pages><volume>55</volume><number>10</number><keywords><keyword>Genetic Predisposition to Disease/genetics</keyword><keyword>*Genetic Techniques</keyword><keyword>Genome-Wide Association Study</keyword><keyword>Humans</keyword><keyword>Mental Disorders/*genetics</keyword><keyword>Multifactorial Inheritance/*genetics</keyword><keyword>Polymorphism, Single Nucleotide/genetics</keyword><keyword>Risk Factors</keyword><keyword>Polygenic risk scoring</keyword><keyword>SNP analyses</keyword><keyword>disease traits</keyword><keyword>genome-wide association studies</keyword><keyword>heritability</keyword><keyword>psychiatric disorders</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1469-7610 (Electronic)
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ADDIN EN.CITE.DATA 14. High quality SNPs was selected to generate the scores that had a MAF > 10%, INFO score > 0.9, a low linkage disequilibrium to each other and excluding all indels and the extended MHC region. The schizophrenia GWAS results of SNPS associated at nine P-value thresholds (5 x 10-8, 1 x 10-6, 1 x 10-4, 0.001, 0.01, 0.05, 0.1, 0.2, 0.5) were selected to compute the polygenic risk scores in our sample. We regressed a model for each polygenic risk score created from various training p-value thresholds against a base model including the first five principal components and any additional principal components from the first 20 that were nominally associated (P < 0.05) with TRP. To assess the proportion of variance explained we computed the R2 on the liability scale ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2012</Year><RecNum>4720</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>4720</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1517825009">4720</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, S. H.</author><author>Goddard, M. E.</author><author>Wray, N. R.</author><author>Visscher, P. M.</author></authors></contributors><auth-address>Queensland Institute of Medical Research, Brisbane, QLD 4072, Australia. Hong.Lee@uq.edu.au.</auth-address><titles><title>A better coefficient of determination for genetic profile analysis</title><secondary-title>Genetic Epidemiology</secondary-title><alt-title>Genet Epidemiol</alt-title></titles><alt-periodical><full-title>Genet Epidemiol</full-title></alt-periodical><pages>214-24</pages><volume>36</volume><number>3</number><keywords><keyword>Case-Control Studies</keyword><keyword>*Genome-Wide Association Study</keyword><keyword>Humans</keyword><keyword>Likelihood Functions</keyword><keyword>*Models, Genetic</keyword><keyword>*Models, Statistical</keyword><keyword>Polymorphism, Single Nucleotide</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1098-2272 (Electronic)
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ADDIN EN.CITE.DATA 6,7. Briefly, PennCNV ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2007</Year><RecNum>4381</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>4381</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1439224524">4381</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, K.</author><author>Li, M.</author><author>Hadley, D.</author><author>Liu, R.</author><author>Glessner, J.</author><author>Grant, S. F.</author><author>Hakonarson, H.</author><author>Bucan, M.</author></authors></contributors><auth-address>Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.</auth-address><titles><title>PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data</title><secondary-title>Genome Research</secondary-title><alt-title>Genome Res</alt-title></titles><periodical><full-title>Genome Res</full-title><abbr-1>Genome research</abbr-1></periodical><alt-periodical><full-title>Genome Res</full-title><abbr-1>Genome research</abbr-1></alt-periodical><pages>1665-74</pages><volume>17</volume><number>11</number><keywords><keyword>*Gene Dosage</keyword><keyword>*Genetic Variation</keyword><keyword>*Genome, Human</keyword><keyword>Genotype</keyword><keyword>Humans</keyword><keyword>*Markov Chains</keyword><keyword>Models, Statistical</keyword><keyword>*Polymorphism, Single Nucleotide</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1088-9051 (Print)
1088-9051 (Linking)</isbn><accession-num>17921354</accession-num><urls><related-urls><url> was used for CNV detection and CNVs called in the same individual were joined together if the distance separating them was less than 50% of their combined length. CNVs were excluded if they were called using fewer than 10 probes, were less than 10KB in size, overlapped segmental duplications by more than 50% of their length, had a probe density of < 1 probe per 20Kb, had a frequency > 1% or were outliers for the following quality control metrics: log R ratio standard deviation, B-allele frequency drift, wave factor and total number of CNVs. To compare the enrichment of rare, pathogenic CNVs in TRP with non-TRP, we analysed (i) the presence of an intellectual disability (ID) pathogenic CNV, defined as any locus associated with ID in Coe et al (2014)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 6. We also analysed the presence of chromosomal deletions and duplication spanning 500kb or 1Mb in length, irrespective of whether it is considered to be pathogenic. No individual within CardiffCOGS had more than one pathogenic CNV and differences between TRP and non-TRP were analysed using Firth’s logistic regression ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2014</Year><RecNum>4715</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>4715</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1517397211">4715</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, X.</author></authors></contributors><auth-address>Program in Public Health, Departments of Preventive Medicine, Biomedical Informatics, and Applied Mathematics and Statistics, Stony Brook University Stony Brook, NY, USA.</auth-address><titles><title>Firth logistic regression for rare variant association tests</title><secondary-title>Frontiers in Genetics</secondary-title><alt-title>Front Genet</alt-title></titles><alt-periodical><full-title>Front Genet</full-title></alt-periodical><pages>187</pages><volume>5</volume><keywords><keyword>Gee</keyword><keyword>association test</keyword><keyword>firth logistic regression</keyword><keyword>penalized likelihood</keyword><keyword>rare variants</keyword></keywords><dates><year>2014</year></dates><isbn>1664-8021 (Print)
1664-8021 (Linking)</isbn><accession-num>24995013</accession-num><urls><related-urls><url> in R. Supplementary Table 1: Diagnoses of study individualsDiagnosisTRP N (Total=561)Non-TRP N (Total=509)Total N (Total=1070)Schizophrenia431 (76.83%)302 (59.33%)733 (68.50%)Schizoaffective depressed66 (11.76%)83 (16.31%)149 (13.93%)Schizoaffective bipolar45 (8.02%)49 (9.63%)94 (8.79%)Other psychotic disorder19 (3.39%)75 (14.73%)94 (8.79%)Supplementary Table 1: DSM-IV or ICD-10 diagnoses of individuals with treatment-resistant schizophrenia (TRP, n = 561), treatment-responsive schizophrenia (non-TRP, n = 509), and the combined total sample (n = 1070). Other psychotic disorder includes: psychotic disorder not otherwise specified, schizophreniform disorder, delusional disorder, and brief psychotic disorder.Supplementary Table 2: Definitions of clinical predictive variablesVariableN (1070)DescriptionDemographics and family backgroundMale sex1069 (99.9%)Sex: 1 = male, 0 = femaleUrbanicity894 (83.6%)The main place of upbringing: 1 = city, 0 = a village or townFamily Hx of schizophrenia923 (86.3%)Family history of schizophrenia in a first or second degree relativeFamily Hx of psychosis, affective or suicide910 (85.0%)Family history of a psychotic disorder, affective disorder or suicide in a first or second degree relativeMother’s age at birth965 (90.2%)Mother’s age at birthFather’s age at birth916 (85.6%)Father’s age at birthPremorbid factorsBirth complications928 (86.7%)Complication with the participant’s birth such as low birth weight, hypoxia or assisted deliveryPregnancy complications893 (83.5%)Complication with their mother’s pregnancy such as prematurity, pre-eclampsia or placental problemsDevelopmental problems951 (88.9%)A failure to thrive or meet developmental milestonesChildhood abuse975 (91.1%)Childhood physical or sexual abuse reported in the Childhood Life Events Questionnaire (CLEQ) delivered at interview PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5VcHRoZWdyb3ZlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVh
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ADDIN EN.CITE.DATA 19Years in education1030 (96.3%)Total years spent in educationHighest level of education1040 (97.2%)Highest educational attainment: 0 = none, 1 = 11+, 2 = CSE, 3 = O-Level or GCSE, 4 = A-level, 5 = Degree, 6 = Post-graduate degreePremorbid IQ (NART)953 (89.1%)Premorbid IQ estimated from the National Adult Reading Test ADDIN EN.CITE <EndNote><Cite><Author>Nelson</Author><Year>1991</Year><RecNum>4723</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>4723</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1518425502">4723</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Nelson, H. E. & Willison, J.</author></authors></contributors><titles><title>The National Adult Reading Test (NART)</title></titles><dates><year>1991</year></dates><pub-location>Windsor, UK</pub-location><publisher>NFER-Nelcon</publisher><urls></urls></record></Cite></EndNote>20 (predicted WAIS-R full scale IQ = 130.6-1.24*NART error score)Poor premorbid social adjustment1016 (95.0%)Poor premorbid social adjustment defined by OPCRIT item 10: difficulty entering or maintaining social relationships, isolation or social withdrawal prior to onset of psychotic symptomsPoor premorbid work adjustment996 (93.1%)Poor premorbid work adjustment defined by OPCRIT item 9: an inability to maintain a job for more than six months, frequent job changes, only sustaining a job well below that expected by educational level, or failing to keep up with studies before onset of illnessIllness presentationDefinite psychosocial stressor within 6m1007 (94.1%)A psychosocial stressor in the six months prior to onset of psychosis defined by OPCRIT item 16: A severely threatening event that occurred prior to onset that was unlikely to have resulted from subject’s own behaviourAge of onset of psychosis1027 (96.0%)Age of onset of psychosis defined by OPCRIT item 4: The age at which treatment was first sought or if earlier when symptoms caused significant impairmentDuration of untreated psychosis (years)996 (93.1%)Duration of untreated psychosis defined by the difference in months between age of the first antipsychotic treatment and age of onset of psychosis (as defined above)Cannabis use in year prior to onset994 (92.9%)Regular cannabis use in the year prior to illness onsetCigarette smoking prior to onset922 (86.2%)Regular cigarette smoking in the year prior to illness onsetInsidious disease onset (1-6)861 (80.5%)The mode of onset of psychosis defined by OPCRIT item 5: 1 = abrupt onset definable to within hours or up to three days, 2 = acute onset definable to within one week, 3 = moderately acute onset definable within one month, 4 = gradual onset over a period up to six months, 5 = Insidious onset over period greater than six monthsSupplementary Table 2: Definitions of variables tested for TRP prediction. Variables were derived from self-report at interview, clinical case notes and OPCRIT ratings ADDIN EN.CITE <EndNote><Cite><Author>Mcguffin</Author><Year>1991</Year><RecNum>4724</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>4724</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1518426025">4724</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mcguffin, P.</author><author>Farmer, A.</author><author>Harvey, I.</author></authors></contributors><auth-address>Inst Psychiat,London Se5 8af,England</auth-address><titles><title>A Polydiagnostic Application of Operational Criteria in Studies of Psychotic Illness - Development and Reliability of the Opcrit System</title><secondary-title>Archives of General Psychiatry</secondary-title><alt-title>Arch Gen Psychiat</alt-title></titles><periodical><full-title>Archives of general psychiatry</full-title><abbr-1>Arch Gen Psychiatry</abbr-1></periodical><pages>764-770</pages><volume>48</volume><number>8</number><keywords><keyword>diagnostic interview</keyword><keyword>twin concordance</keyword><keyword>schizophrenia</keyword><keyword>reanalysis</keyword></keywords><dates><year>1991</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0003-990x</isbn><accession-num>WOS:A1991GA24600013</accession-num><urls><related-urls><url><Go to ISI>://WOS:A1991GA24600013</url></related-urls></urls><language>English</language></record></Cite></EndNote>5.Supplementary Table 3: Definitions of lifetime clinical variablesVariableN (1070)DescriptionDemographicsMarried or cohabiting1043 (97.5%)Ever been married or lived as married (cohabiting)Have a child611 (57.1%)Ever had a childClinical detailsSchizophrenia diagnosis1069 (99.9%)A schizophrenia diagnosis defined by a DSM-IV or ICD-10 diagnosis of schizophrenia or schizoaffective disorder, depressed typeNo. of psychiatric hospital admissions1054 (98.5%)Total number of psychiatric hospital admissions, including inpatient, day hospital and intensive home treatment by the crisis teamDetained under MHA1065 (99.5%)Ever detained under section 2 or 3 of the Mental Health ActCourse of disorder 1037 (96.9%)Course of disorder as defined by OPCRIT item 90 (1 = single episode with good recovery, 2 = multiple episodes with good recovery between, 3 = multiple episodes with partial recovery between, 4 = continuous chronic illness, 5 = continuous chronic illness with deterioration)Deterioration from premorbid level of functioning1045 (97.7%)Deterioration from premorbid level of functioning defined as OPCRIT item 88 (patient does not regain premorbid social, occupational or emotional functioning after an acute episode of illness)Lowest ever GAS 1052 (98.3%)Lifetime worst Global Assessment Scale (GAS) ADDIN EN.CITE <EndNote><Cite><Author>Endicott</Author><Year>1976</Year><RecNum>4279</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>4279</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1438073067">4279</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Endicott, J.</author><author>Spitzer, R. L.</author><author>Fleiss, J. L.</author><author>Cohen, J.</author></authors></contributors><titles><title>The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance</title><secondary-title>Archives of General Psychiatry</secondary-title><alt-title>Arch Gen Psychiatry</alt-title></titles><periodical><full-title>Archives of general psychiatry</full-title><abbr-1>Arch Gen Psychiatry</abbr-1></periodical><alt-periodical><full-title>Archives of general psychiatry</full-title><abbr-1>Arch Gen Psychiatry</abbr-1></alt-periodical><pages>766-71</pages><volume>33</volume><number>6</number><keywords><keyword>Hospitalization</keyword><keyword>Humans</keyword><keyword>Mental Disorders/*diagnosis</keyword><keyword>*Psychiatric Status Rating Scales</keyword><keyword>Psychometrics</keyword></keywords><dates><year>1976</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0003-990X (Print)
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ADDIN EN.CITE.DATA 4, imputed and standardised into z-scoresClinical symptomsLifetime depressive episode954 (89.2%)Lifetime depressive episode lasting a minimum of two weeksLifetime manic episode1020 (95.3%)Lifetime manic episode lasting a minimum of 4 daysSeverity of negative symptoms1034 (96.6%)Severity of positive symptoms defined as total sum of global lifetime ratings from the scale for the assessment of positive symptoms ADDIN EN.CITE <EndNote><Cite><Author>Andreasen</Author><Year>1984</Year><RecNum>4273</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>4273</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1438008008">4273</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Andreasen, Nancy C</author></authors></contributors><titles><title>Scale for the assessment of positive symptoms</title></titles><dates><year>1984</year></dates><pub-location>Iowa City, IA</pub-location><publisher>University of Iowa Press</publisher><urls></urls></record></Cite></EndNote>22 (SAPS total = global hallucinations + global delusions + global bizarre behaviour + global positive formal thought disorder)Severity of positive symptoms1039 (97.1%)Severity of negative symptoms defined as total sum of global lifetime ratings from the scale for the assessment of negative symptoms ADDIN EN.CITE <EndNote><Cite><Author>Andreasen</Author><Year>1983</Year><RecNum>4275</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1438008563">4275</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Andreasen, Nancy C</author></authors></contributors><titles><title>Scale for the assessment of negative symptoms</title></titles><dates><year>1983</year></dates><pub-location>Iowa City, IA</pub-location><publisher>The University of Iowa Press</publisher><urls></urls></record></Cite></EndNote>23 (SANS total = global affective flattening + global alogia + global avolition apathy + global anhedonia asociality)Substance useLifetime regular smoker1045 (97.7%)Ever been a regular tobacco smokerLifetime alcohol abuse964 (90.1%)Lifetime alcohol abuse defined by OPCRIT item 78: continued use for at least one month despite knowledge of having a persistent or recurrent social, occupational, psychological or physical problem that is caused or exacerbated by alcohol or recurrent use in situations in which it is physically hazardous; or symptoms definitely indicative of dependenceLifetime regular cannabis use1032 (96.4%)Lifetime regular cannabis use defined as persistent use for one month or repeated use (i.e. one a week) within one yearLifetime regular drug use1023 (95.6%)Lifetime regular unspecified drug use defined as persistent use for one month or repeated use (i.e. one a week) within one yearSupplementary Table 3: Definitions of variables related to demographics, lifetime clinical characteristics, clinical symptoms and substance use. Variables were derived from self-report at interview, clinical case notes and OPCRIT ratings ADDIN EN.CITE <EndNote><Cite><Author>Mcguffin</Author><Year>1991</Year><RecNum>4724</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>4724</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1518426025">4724</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mcguffin, P.</author><author>Farmer, A.</author><author>Harvey, I.</author></authors></contributors><auth-address>Inst Psychiat,London Se5 8af,England</auth-address><titles><title>A Polydiagnostic Application of Operational Criteria in Studies of Psychotic Illness - Development and Reliability of the Opcrit System</title><secondary-title>Archives of General Psychiatry</secondary-title><alt-title>Arch Gen Psychiat</alt-title></titles><periodical><full-title>Archives of general psychiatry</full-title><abbr-1>Arch Gen Psychiatry</abbr-1></periodical><pages>764-770</pages><volume>48</volume><number>8</number><keywords><keyword>diagnostic interview</keyword><keyword>twin concordance</keyword><keyword>schizophrenia</keyword><keyword>reanalysis</keyword></keywords><dates><year>1991</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0003-990x</isbn><accession-num>WOS:A1991GA24600013</accession-num><urls><related-urls><url><Go to ISI>://WOS:A1991GA24600013</url></related-urls></urls><language>English</language></record></Cite></EndNote>5.Supplementary Table 4: Characteristics of participants with missing dataComplete dataMissing dataOR (95% CI)PN (%) or mean (s.d.)Total NN (%) ormean (s.d)Total NMale sex206 (61.1%)337456 (62.2%)7330.96 (0.73-1.25)0.735Age at interview42.47 (sd=12.1)37743.40 (sd=11.9)7330.99 (0.98-1.00)0.238Systematic recruitment227 (67.4%)337537 (73.4%)7320.75 (0.57-0.99)0.044Treatment-resistant schizophrenia152 (45.1%)337409 (55.8%)7330.65 (0.50-0.84)1.18x10-3Supplementary Table 4: Characteristics of study participants with missing data. Columns represent characteristics of those with complete data, those with incomplete data (reference group), odds ratio (OR), 95% confidence intervals (CI), and P-value from univariate logistic regression. For binary variables, numbers (N) and percentages (%) are given, and for continuous variables, mean and standard deviation (sd) measures are given. Supplementary Table 5: Lifetime characteristicsTRPNon-TRPOR (95% CI)PN (%) or mean (s.d.)Total NN (%) ormean (s.d)Total NDemographicsMarried or cohabiting143 (26.3%)544181 (36.3%)4990.73 (0.55-0.97)0.027Have a child104 (32.7%)318127 (43.3%)2930.68 (0.48-0.97)0.035Clinical detailsSchizophrenia diagnosis431 (76.8%)561302 (59.4%)5082.11 (1.61-2.76)6.64x10-8No. of psychiatric hospital admissions6.32 (sd=7.2)5513.79 (sd=4.7)5031.12 (1.08-1.15)6.05x10-12Detained under MHA378 (67.9%)557288 (56.7%)5081.63 (1.26-2.10)2.02x10-4Course of disorder 4.86 (sd=1.2)5443.61 (sd=1.3)4932.14 (1.91-2.41)7.55x10-38Deterioration from premorbid level of functioning535 (96.1%)557416 (85.2%)4884.57 (2.75-7.59)4.23x10-9Lowest ever GAS 18.65 (sd=6.8)55322.55 (sd=7.9)4990.93 (0.92-0.95)1.41x10-13IQ (MATRICS composite)-2.58 (sd=1.3)538-1.93 (sd=1.28)4670.62 (0.56-0.70)3.88x10-16Clinical symptomsLifetime depressive episode323 (65.3%)495335 (73.0%)4590.69 (0.52-0.92)0.010Lifetime manic episode75 (14.0%)53668 (14.0%)4841.04 (0.72-1.49)0.840Severity of negative symptoms7.91 (sd=4.1)5366.47 (sd=4.2)4981.09 (1.06-1.12)6.02x10-8Severity of positive symptoms9.78 (sd=3.1)5408.67 (sd=2.9)4991.13 (1.08-1.18)2.65x10-8Substance useLifetime regular smoker434 (79.8%)544360 (71.9%)5011.56 (1.16-2.09)2.96x10-3Lifetime alcohol abuse153 (30.1%)508125 (27.4%)4561.21 (0.91-1.62)0.187Lifetime regular cannabis use243 (45.2%)538181 (36.6%)4941.35 (1.03-1.77)0.031Lifetime regular drug use183 (34.3%)533135 (27.6%)4901.23 (0.92-1.64)0.156Supplementary Table 5: Lifetime characteristics of study participants with treatment-responsive schizophrenia (non-TRP) and treatment-resistant schizophrenia (TRP). Columns represent characteristics of non-TRP (reference group), TRP, odds ratio (OR), 95% confidence intervals (CI), and P-value from univariate logistic regression adjusted for age at interview and method of recruitment. For binary variables, numbers (N) and percentages (%) were given, and for continuous variables, mean and standard deviation (sd) measures were given. P-values in bold survived correction for multiple testing (p < 2.94x10-3).Supplementary Table 6: Lifetime clinical characteristics (SZ only)TRPNon-TRPOR (95% CI)PN (%) or mean (s.d.)Total NN (%) ormean (s.d)Total NDemographicsEver married121 (25.1%)483130 (34.4%)3780.75 (0.54-1.03)0.073Having a child89 (32.0%)278100 (43.5%)2300.66 (0.44-0.98)0.037Clinical detailsSchizophrenia diagnosis------No. psychiatric hospital admissions6.11(sd=7.13)4874.00 (sd=5.00)3801.09 (1.05-1.12)3.62x10-7Ever sectioned under MHA332 (67.2%)494225 (58.4%)3851.46 (1.10-1.94)8.92x10-3Course of disorder 4.90 (sd=1.21)4873.79 (sd=1.30)3752.03 (1.79-2.31)8.53x10-28Deterioration from premorbid level of functioning479 (97.0%)494330 (89.2%)3704.25 (2.27-7.966.00x10-6Lowest ever GAS 18.61 (sd=6.76)48921.88 (sd=7.27)3790.94 (0.92-0.96)1.06x10-8IQ (MATRICS composite)-2.61 (sd=1.34)475-2.07 (sd=1.30)3530.67 (0.59-0.75)1.02x10-10Clinical symptomsLifetime depressive episode269 (61.6%)437242 (69.5%)3480.70 (0.51-0.95)0.020Lifetime manic episode35 (7.3%)47818 (4.9%)3681.45 (0.80-2.63)0.225Severity of negative symptoms7.98 (sd=4.15)4756.94 (sd=4.16)3771.07 (1.03-1.10)2.45x10-4Severity of positive symptoms9.91 (sd=3.06)4788.90 (sd=2.86)3781.12 (1.07-1.17)6.00x10-6Substance useLifetime regular smoker387 (79.8%)485279 (73.2%)3811.43 (1.03-1.97)0.033Lifetime alcohol abuse132 (29.1%)45392 (26.7%)3441.19 (0.86-1.65)0.289Lifetime regular cannabis use125 (39.2%)480181 (44.7%)3721.18 (0.87-1.59)0.287Lifetime regular drug use164 (34.4%)477108 (29.3%)3691.10 (0.81-1.51)0.538Supplementary Table 6: Analyses of lifetime clinical characteristics for participants with treatment-resistant psychosis (TRP) and treatment-responsive psychosis (non-TRP) restricted to those with a schizophrenia or schizoaffective disorder, depressed type diagnosis. Columns represent characteristics of TRP, non-TRP (reference group), odds ratio (OR), 95% confidence intervals (CI), and P-value from univariate logistic regression adjusted for age at interview and method of recruitment. For binary variables, numbers (N) and percentages (%) are given, and for continuous variables, mean and standard deviation (sd) measures are given. P-values in bold survive correction for multiple testing (p < 2.94x10-3). Supplementary Table 7: Clinical predictors of TRP (SZ only)TRPNon-TRPAdjusted Univariate (up to N=935)Fully Adjusted Multivariate (N=510)N (%) / mean (sd)Total NN (%) / mean (sd)Total NOR (95% CI)POR (95% CI)PDemographics and family backgroundMale sex333 (67.0%)497247 (64.2%)3851.12 (0.84-1.50)0.4280.92 (0.60-1.39)0.681Urbanicity (city birth and upbringing)156 (39.4%)396137 (40.5%)3381.03 (0.76-1.40)0.860Family Hx of schizophrenia114 (26.8%)42575 (22.5%)3331.25 (0.88-1.76)0.2090.90 (0.58-1.41)0.654Family Hx of psychosis, affective or suicide220 (52.9%)416186 (55.9%)3330.83 (0.61-1.12)0.222Mother’s age at birth26.63 (sd=6.3)43526.87 (sd=6.2)3571.00 (0.97-1.02)0.745Father’s age at birth29.33 (sd=7.3)41730.02 (sd=7.6)3360.99 (0.97-1.01)0.2290.98 (0.95-1.00)0.069Premorbid factorsBirth complications100 (23.8%)42071 (21.0%)3381.17 (0.82-1.67)0.382Pregnancy complications40 (9.9%)40527 (8.3%)3241.22 (0.72-2.07)0.463Developmental problems86 (20.0%)43162 (18.0%)3441.16 (0.80-1.68)0.447Childhood abuse88 (19.4%)45475 (20.7%)3620.94 (0.66-1.34)0.720Years in education12.70 (sd=3.6)47913.12 (sd=2.9)3710.96 (0.91-1.00)0.0670.98 (0.93-1.04)0.582Highest level of education2.53 (sd=1.7)4812.76 (sd=1.8)3780.92 (0.85-1.00)0.0461.07 (0.92-1.25)0.383Premorbid IQ (NART)96.78 (sd=13.5)45699.53 (sd=13.3)3610.99 (0.98-1.00)0.0450.98 (0.97-1.00)0.070Poor premorbid social adjustment216 (45.5%)475127 (34.9%)3641.56 (1.17-2.10)2.44x10-31.74 (1.14-2.65)0.010Poor premorbid work adjustment108 (23.7%)45557 (15.7%)3621.56 (1.09-2.25)0.0171.32 (0.78-2.24)0.301Illness presentationDefinite psychosocial stressor within 6 m33 (7.1%)46537 (10.1%)3650.70 (0.42-1.16)0.1620.74 (0.36-1.51)0.401Age of onset of psychosis22.92 (sd=8.0)48027.10 (sd=9.9)3660.95 (0.93-0.97)3.08x10-80.96 (0.93-0.98)1.84x10-3Duration of untreated psychosis (years)2.14 (sd=4.6)4672.03 (sd=4.2)3571.01 (0.98-1.04)0.487Cannabis use in year prior to onset172 (37.1%)46396 (26.7%)3591.46 (1.06-2.03)0.0221.60 (1.02-2.52)0.041Cigarette smoking prior to onset273 (65.6%)416219 (62.9%)3481.12 (0.83-1.52)0.453Insidious disease onset (1-6)3.66 (sd=1.4)3843.61 (sd=1.4)3210.97 (0.87-1.09)0.624Supplementary Table 7: Association of clinical predictors with treatment-resistant psychosis (TRP) restricted to individuals with a schizophrenia or schizoaffective disorder, depressed type diagnosis. Columns represent clinical variables, TRP, non-TRP (reference group), odds ratio (OR), 95% confidence intervals (CI) and P-value from univariate logistic regression adjusted for age at interview and method of recruitment, and adjusted multivariate logistic regression. For binary variables, numbers (N) and percentages (%) are provided, and for continuous variables, mean and standard deviation (sd) are provided. P-values in bold survived correction for multiple testing (p < 2.38x10-3).Supplementary Table 8: Multivariate model (N=337)Fully Adjusted Multivariate (N=337)OR (95% CI)PDemographics and family backgroundMale sex1.14 (0.66-1.97)0.645Urbanicity (city birth and upbringing)1.13 (0.68-1.90)0.631Family Hx of schizophrenia1.22 (0.63-2.39)0.557Family Hx of psychosis, affective or suicide0.45 (0.25-0.79)5.19x10-3Mother’s age at birth1.07 (1.00-1.15)0.066Father’s age at birth0.93 (0.87-0.99)0.015Premorbid factorsBirth complications1.08 (0.57-2.06)0.808Pregnancy complications1.17 (0.44-3.12)0.759Developmental problems0.42 (0.20-0.90)0.026Childhood abuse1.45 (0.71-2.93)0.298Years in education1.00 (0.88-1.13)0.941Highest level of education1.02 (0.81-1.28)0.867Premorbid IQ (NART)0.98 (0.96-1.01)0.141Poor premorbid social adjustment3.02 (1.66-5.49)2.91x10-4Poor premorbid work adjustment1.45 (0.67-3.12)0.349Illness presentationDefinite psychosocial stressor within 6 m0.97 (0.39-2.39)0.947Age of onset of psychosis0.93 (0.89-0.97)2.70x10-4Duration of untreated psychosis (years)0.96 (0.89-1.03)0.222Cannabis use in year prior to onset1.46 (0.79-2.67)0.227Cigarette smoking prior to onset1.07 (0.59-1.96)0.819Insidious disease onset (1-6)0.95 (0.79-1.15)0.614Supplementary Table 8: Association of clinical predictors with TRP restricted to individuals with no missing data (n=377) for direct comparison with machine-learning analyses.Supplementary Table 9: Schizophrenia PRS and TRP (SZ only)Score P-value ThresholdOR (95% CI)R2AUCSEP-value P < 1 x 10-81.07 (0.92-1.24)0.00110.5160.00280.387P < 1 x 10-61.06 (0.91-1.23)0.00090.5140.00250.447P < 1 x 10-41.04 (0.89-1.21)0.00040.5090.00170.647P < 1 x 10-31.15 (0.97-1.35)0.00500.5330.00590.099P < 0.011.12 (0.94-1.34)0.00310.5260.00460.212P < 0.051.13 (0.93-1.37)0.00300.5260.00460.214P < 0.11.11 (0.91-1.36)0.00240.5230.00400.283P < 0.21.18 (0.96-1.45)0.00460.5320.00560.124P < 0.51.13 (0.91-1.40)0.00250.5230.00420.272Supplementary Table 9: Analysis of association of schizophrenia polygenic risk score (PRS) with TRP only including individuals with a schizophrenia or schizoaffective disorder, depressed type diagnosis (n=694 total). Columns represent the p-value threshold used in discovery cohort to derive scores, odds ratio (OR) and 95% confidence intervals, R2 calculated on the liability scale ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2012</Year><RecNum>4720</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>4720</rec-number><foreign-keys><key app="EN" db-id="vfrazzdppe9w9ueee5x5ew0g005r90epvwfs" timestamp="1517825009">4720</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, S. H.</author><author>Goddard, M. E.</author><author>Wray, N. R.</author><author>Visscher, P. M.</author></authors></contributors><auth-address>Queensland Institute of Medical Research, Brisbane, QLD 4072, Australia. Hong.Lee@uq.edu.au.</auth-address><titles><title>A better coefficient of determination for genetic profile analysis</title><secondary-title>Genetic Epidemiology</secondary-title><alt-title>Genet Epidemiol</alt-title></titles><alt-periodical><full-title>Genet Epidemiol</full-title></alt-periodical><pages>214-24</pages><volume>36</volume><number>3</number><keywords><keyword>Case-Control Studies</keyword><keyword>*Genome-Wide Association Study</keyword><keyword>Humans</keyword><keyword>Likelihood Functions</keyword><keyword>*Models, Genetic</keyword><keyword>*Models, Statistical</keyword><keyword>Polymorphism, Single Nucleotide</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1098-2272 (Electronic)
0741-0395 (Linking)</isbn><accession-num>22714935</accession-num><urls><related-urls><url> , area under the curve (AUC), standard error (SE), and P-value of association of each score of with TRP.Supplementary Table 10: CNVs and TRP (SZ only)TRP N (%)Total = 380Non-TRP N (%) Total = 307OR (95% CI)PIntellectual disability pathogenic CNV9 (2.4%)11 (3.6%)0.66 (0.27-1.58)0.348Schizophrenia pathogenic CNV7 (1.8%)11 (3.6%)0.52 (0.19-1.30)0.161>500kb deletion10 (2.6%)9 (2.9%)0.89 (0.36-2.21)0.799>1Mb deletion4 (1.1%)0 (0.0%)2.78 (0.78-975.5)0.088>500kb duplication31 (8.2%)25 (8.1%)1.00 (0.58-1.73)0.996>1Mb duplication8 (2.1%)13 (4.2%)0.50 (0.20-1.17)0.111Supplementary Table 10: Association analysis of CNVs with TRP restricted to study individuals with a schizophrenia or schizoaffective disorder, depressed type diagnosis (n=634 total). Columns represent CNVs assessed (intellectual disability (ID) pathogenic CNVPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db2U8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 24, deletions spanning 500kb or 1Mb in length, and duplications spanning 500kb or 1Mb in lengths), frequencies of each CNV in non-TRP (reference group), TRP, odds ratio (OR), 95% confidence intervals (CI) and P-value from Firth’s logistic regression. Supplementary Table 11: Proportion of TRP by age of onset of psychosisAge of onsetTRPNon-TRPTotalProportion TRP<=12185230.7814218290.7215159240.63162818460.61172919480.60183219510.63193111420.74203522570.61214121620.66224024640.63233316490.67241817350.51251936550.35261519340.44272416400.60281822400.45291720370.46301416300.47322120410.51342025450.44361727440.39381319320.4140719260.2745730370.1960525300.17Total53848310210.53Supplementary Table 11: Proportion of study individuals with TRP by age of onset of psychosis (data used for Figure 2). Columns represent age of onset of psychosis, the number with TRP, number with non-TRP, total sample size, and the proportion with TRP (TRP/Total) for each age of onset group. Supplementary Table 12: Predictive analysis of age of onset of psychosisAgeSensitivitySpecificityPPVNPVAdjusted PPVAdjusted NPV< 160.900.050.290.510.510.2916 – 200.710.180.360.490.600.2721 – 250.720.240.430.510.660.2926 – 300.840.190.510.540.730.3131 – 400.860.230.590.550.790.3241 +0.980.110.820.550.920.32Supplementary Table 12: Predictive analysis for age of onset of psychosis and non-TRP (total n=1021). Columns represent age of onset of psychosis, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), PPV adjusted for prevalence rate of TRP in schizophrenia (30%), and NPV adjusted for prevalence rate of TRP in schizophrenia (30%).Supplementary Table 13: Schizophrenia PRS and age of onset Score P-value ThresholdBeta (95% CI)R2SEP-value P < 1 x 10-8-0.32 (-0.96-0.32)0.00120.3260.333P < 1 x 10-6-0.73 (-1.37--0.85)0.00610.3280.027P < 1 x 10-4-0.69 (-1.35--0.04)0.00530.3330.037P < 1 x 10-3-0.59 (-1.28-0.09)0.00350.3490.090P < 0.01-0.86 (-1.62-0.10)0.00600.3890.027P < 0.05-0.74 (-1.56-0.09)0.00370.4210.080P < 0.1-0.73 (-1.58-0.12)0.00350.4320.091P < 0.2-0.87 (-1.75-0.01)0.00460.4480.052P < 0.5-0.74 (-1.65-0.16)0.00320.4620.108Supplementary Table 13: Analysis of association of schizophrenia polygenic risk score (PRS) with age of onset of psychosis (total n=814). Columns represent the p-value threshold used in discovery cohort to derive scores, odds ratio (OR) and 95% confidence intervals, R2, area under the curve (AUC), standard error (SE), and P-value of association of each score of with age of onset of psychosis.Supplementary Table 14: Schizophrenia PRS and age of onset (SZ only)Score P-value ThresholdBeta (95% CI)R2SEP-value P < 1 x 10-8-0.21 (-0.87-0.45)0.00060.3380.534P < 1 x 10-6-0.55 (-1.22-0.12)0.00390.3410.107P < 1 x 10-4-0.51 (-1.18-0.17)0.00320.3460.145P < 1 x 10-3-0.34 (-1.05-0.36)0.00140.3600.340P < 0.01-0.82 (-1.61--0.04)0.00640.4000.040P < 0.05-0.87 (-1.71--0.03)0.00630.4280.042P < 0.1-0.92 (-1.78--0.06)0.00660.4390.037P < 0.2-1.01 (-1.90--0.12)0.00750.4550.026P < 0.5-0.90 (-1.81-0.02)0.00550.4680.056Supplementary Table 14: Analysis of association of schizophrenia polygenic risk score (PRS) with age of onset of psychosis restricted to study individuals with a schizophrenia or schizoaffective disorder, depressed type diagnosis (total n=663). Columns represent the p-value threshold used in discovery cohort to derive scores, odds ratio (OR) and 95% confidence intervals, R2, area under the curve (AUC), standard error (SE), and P-value of association of each score of with age of onset of psychosis.Supplementary Figure 1: Correlation matrix of clinical predictive variables Supplementary Figure 1: Correlation matrix of 21 clinical predictive variables produced by the ‘corrplot’ R package. Positive correlations are displayed in blue and negative correlations in red. Colour intensity and the size of the circle are proportional to the correlation coefficients.Supplementary Figure 2: Conditional inference forests model (SZ only)Supplementary Figure 2: Variable importance plots from conditional inference forests models predicting TRP restricted to those with a schizophrenia or schizoaffective disorder, depressed type diagnosis. References ADDIN EN.REFLIST 1.Lynham AJ, Hubbard L, Tansey KE, et al. 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