Cognitive subgrouping in people with schizophrenia and their unaffected siblings Dwight Dickinson1, Evan Giangrande1, Daniel R. Weinberger2, Karen F. Berman1 1Clinical and Translational Neuroscience Branch, NIMH NIH, Bethesda, MD, USA 2Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA Heterogeneity in schizophrenia has led to a search for ways to divide the diagnostic category into subgroups relevant to etiology, course, and/or treatment response. Current analyses examined a subgrouping scheme advanced by Weickert et al. (2001), based on indicators of current and pre-morbid cognitive performance, which yielded subgroups labeled as showing “compromised,” “deteriorated,” or “preserved” cognition in earlier work. INTRODUCTION RESULTS and CONCLUSIONS RESULTS and CONCLUSIONS The reality of clustering approaches in schizophrenia Cognition vs. Symptoms Not tidy, well-separated classes – fuzzy-bordered, overlapping classes Reflection of heterogeneous biology and complex interactions that shape phenotype But identification of relatively homogeneous subgroups, could still improve traction for biology/etiology investigations E.g., genetics models – lower power but, maybe, reduced heterogeneity “g” PANSS Total METHODS Comprehensive assessment data for 558 people with schizophrenia (Sz), 305 unaffected siblings (Sib), and 1128 community controls (Ctrl), were available from the NIMH/CBDB Study of Genetic Risk for Schizophrenia. In the Sz sample, an unsupervised two-step clustering procedure, with estimated pre-morbid IQ (WRAT reading) and current full scale IQ (est. WAIS IQ) indicators, suggested three subgroups, as in earlier work. K-means clustering was used to derive cluster designations for the three subgroups for Sz. To examine the consistency of the cognitive subgroup assignments within families, subgroup designations from the affected Sz were also assigned to unaffects Sibs. Error bar graphs and GLM analyses compared Ctrl with Sz and Sib cognitive subgroups on selected variables, controlling for age, sex and race. GLM repeated measures analyses were used in analyses of affected/unaffected sibling pairs. Across a comprehensive battery, the schizophrenia HH group performs at the low end of the sibling range and are far less impaired than other cases Schz HL are intermediate, closer to the LL than the HH Schz HH are also less symptomatic than other cases but differences across subgroups are modest A focus on affected and unaffected siblings (~110 pairs) from the two “High High” groups only WRAT Extending the analyses to include unaffected siblings and controls It is not accurate to characterize the best performing schizophrenia cases as “cognitively preserved” or “neuro- psychologically normal” Even when cognitive performance is within so-called normal limits, individuals are substantially impaired relative to their own unaffected siblings While functioning is profoundly compromised F = 0.05 p = .82 Schz Generally, except in the case of WRAT, the two low performing schizophrenia groups are fairly close The group that differs most cognitively is the Schz HH group Sib subgroup performance holds to pattern Sib subgroup configuration is less consistent Schz Sibs IQ Sibs 3 schizophrenia ‘subgroups’ from clustering: IQ WRAT IQ F = 18.35 p = 4.0E-05 “g” WRAT Digit Symbol F = 51.50 p = 9.2E-11   SzLowLow SzHighLow SzHighHigh SibLowLow SibHighLow SibHighHigh Control N 132 329 98 61 185 59 1127 Proportion Female 0.27 0.22 0.39 0.61 0.51 0.63 0.56 Proportion Caucasian 0.68 0.84 0.91 0.85 0.87 0.93 0.72 Age Mean 31.85 33.61 38.08 32.98 34.64 38.03 30.68 SD 8.81 9.95 9.81 9.30 9.36 8.54 9.20 Years of Education 12.93 13.97 15.48 15.11 15.94 16.95 16.47 1.95 2.05 2.14 2.50 2.19 2.34 2.47 GAF 43.39 45.45 51.82 84.74 85.45 84.69 87.56 13.05 13.60 14.73 7.62 6.19 7.66 3.51 WAIS Est Full Scale IQ 82.90 90.65 109.20 102.34 105.95 111.05 107.07 8.04 7.81 5.22 10.21 9.99 10.28 WRAT Reading Score 86.22 105.10 112.06 101.54 107.72 110.71 107.77 7.31 6.59 5.92 10.93 8.92 8.90 9.51 PANSS Total 63.22 58.84 50.33 30.92 31.89 32.92 30.75 21.29 21.59 19.83 1.87 3.96 6.67 2.35 GAF Benton Line F = 366.95 p = 4.5E-35 For some measures – WRAT, Benton Line – HH Schz and Sibs match or exceed control performance For others – Digit Symbol, verbal memory – all Schz and Sib groups are impaired Contact: Dwight.Dickinson@nih.gov