1. 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 =
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
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