PsychiatryResearch, 38: 115-124 Elsevier
Genetic Study
115
Factors for the Span of Apprehension of Normal Twins
Aniko Bartfai, Nancy L. Pedersen,
Robert F. Asarnow,
Test: A
and Daisy Schalling
Received March 22, 1990; revised version received November 26, 1990; accepted February 3, 1991. Abstract. The Partial Report Span of Apprehension test has been found to detect cognitive deficits in some first degree relatives of schizophrenic patients. TO assess
the relative contribution of genetic vs. environmental factors on this measure, 19 monozygotic and 14 dizygotic female twin pairs, selected from a normal population, were tested on the Span of Apprehension test and an IQ test. Both Span of Apprehension test performance and IQ score had high heritabilities: 0.65 and 0.7 1, respectively. The mode of transmission for performance on the Span of Apprehension test appears to operate in a nonadditive manner. A multivariate behavioral-genetic model applied to the Span of Apprehension and IQ measures indicated that slightly less than half of the genetic effects important for the Span of Apprehension test are found in common with the genetic factors important for IQ. The phenotypic correlation between the Span of Apprehension and IQ measures can be attributed entirely to genetic factors. The influence of unique genetic components in the performance of the Span of Apprehension test in the general population heightens the promise of this measure as a genetic marker for schizophrenia.
Key Words. Span of Apprehension,
vulnerability,
IQ, twin study, schizophrenia.
A critical step in elucidating the mechanism(s) for the transmission of schizophrenia is determining precisely what is transmitted. It is now generally accepted that schizophrenia is familially transmitted and that what is transmitted extends beyond psychotic symptoms, also including certain personality disorders. The precise phenotype for the schizophrenic disorders, however, has yet to be clearly defined (Gottesman and Shields, 1982; Kendler, 1988). The lack of a clear definition has stimulated efforts to find sensitive measures of schizophrenic phenotype(s). One promising area of investigation focuses on information processing tasks that are thought to tap the subtle central nervous system (CNS) defects hypothesized to underlie schizophrenic symptoms. A number of information processing tasks that
Aniko Bartfai, Ph.D., is Senior Lecturer, Department of Psychology,
Stockholm University, and Researcher, Department of Psychiatry and Psychology, Karolinska Institute, Stockholm, Sweden. Nancy L. Pedersen, Ph.D., is Associate Professor, Department of Environmental Hygiene, Karolinska Institute, Stockholm, Sweden. Robert F. Asarnow, Ph.D., is Professor, Department of Psychiatry, Neuropsychiatric Institute, UCLA School of Medicine, Los Angeles, CA, USA. Daisy Schalling, Ph.D., is Professor, Department of Psychology, Stockholm University, and Department of Psychiatry and Psychology, Karolinska Institute, Stockholm, Sweden. (Reprint requests to Dr. A. Bartfai, Dept. of Psychiatry and Psychology, Karolinska Hospital, 104 01 Stockholm, Sweden.) 0165-1781191
jSO3.50 @ 1991 Elsevier Scientific
Publishers
Ireland
Ltd.
116 require rapid processing of information have detected dysfunctions in nonpsychotic first degree relatives of schizophrenic probands (for reviews, see R.F. Asarnow, 1983; Nuechterlein and Dawson, 1984; Holzman, 1987; J.R. Asarnow, 1988). One particularly promising task is the Partial Report Span of Apprehension test (Estes and Taylor, 1966), which measures the amount of information extracted from briefly presented visual displays. While the results of a few studies (e.g., Strauss et al., 1984; Prescott et al., 1991) cast doubt upon the specificity of deficits in performance on the Span of Apprehension test to schizophrenia, a recent review (Asarnow et al., in press) reveals that (1) seven of eight studies found that schizophrenic patients performed significantly worse than normal subjects, and (2) three of four studies found significant differences between schizophrenic patients and psychiatric contrast groups. Both foster-reared children whose biological mothers were schizophrenic (Asarnow et al., 1977) and the nonpsychotic mothers of schizophrenic probands (Wagener et al., 1986) also show deficits in this task. The current data, with some few exceptions, suggest that the Span of Apprehension test may meet Spring and Zubin’s (1978) criteria for measures of the genetic liability to schizophrenic disorder. According to Spring and Zubin, such a measure should detect deficits in individuals generally at risk but not necessarily schizophrenic, and should show concordance among ill schizophrenic patients, their healthy siblings, and schizophrenic patients in remission. While the presence of information processing impairments in the first degree relatives of schizophrenic probands is consistent with the hypothesis that the Span of Apprehension test may be a sensitive measure of the schizophrenic phenotype, familial aggregation does not necessarily demonstrate genetic transmission. Shared environmental factors could also be involved. One powerful method to separate shared familial environments from genetic effects is the comparison of monozygotic twins reared together with those reared apart (Gottesman and Shields, 1982). To our knowledge, this method has not yet been applied to the Span of Apprehension test. The present study compared the similarity between the Span of Apprehension performance of normal monozygotic and dizygotic twins reared together and monozygotic twins reared apart to determine the extent to which individual differences in Span of Apprehension performance in normal subjects are heritable. Scores on the Span of Apprehension test are not highly correlated with estimates of IQ in schizophrenic probands (Asarnow et al., in press), but the presence of an association in a normal population has not yet been examined. If a strong association were found, it would indicate that the Span of Apprehension test is simply tapping the abilities summarized by IQ, and thus would diminish its possible importance as an independent marker of vulnerability. One purpose of the present study was to determine the extent of the correlation between Span of Apprehension and IQ measures in a normal population. A number of cognitive abilities are heritable in the general population (Vandenberg and Vogler, 1985), including the broad set of abilities indexed by tests of general intellectual ability (IQ). An analysis of the genetic effects for the Span of Apprehension test uncorrected for IQ could in part reflect genetic effects for IQ. The present study, therefore, attempted to assess the total importance of genetic effects for Span of Apprehension performance, as well as genetic effects unique to the task, that are independent of IQ.
117
Methods Subjects. The subjects were drawn from the ongoing Swedish Adoption/Twin Study of Aging (SATSA; for details, see Pedersen et al., 1984, 1988; McClearn et al., in press), which includes all twins from the population based Swedish Twin Register who were separated at an early age and reared apart and a matched sample of twins reared together. All female pairs under 50 years of age in which both members responded to a mailout questionnaire in 1984 were considered for participation. Pairs were contacted on a random basis until the quota of 10 pairs of monozygotic twins reared apart (MZA), 10 pairs of monozygotic twins reared together (MZT), and 15 pairs of dizygotic twins reared together (DZT) was met. At this point, a preliminary zygosity diagnosis was based on responses to questionnaire items concerning physical similarity. Subjects were contacted by letter and later by phone by a research assistant, who informed them about the purpose of the study and explained procedures. Only pairs in which both twins were willing to participate were brought into a central testing location at the Karolinska Hospital in Stockholm. The refusal rate was 31%. Reasons for refusal include not being able to leave jobs (shop owners), no help in taking care of small children, and the inconvenience of traveling to Stockholm. Only three subjects refused because of lack of interest. There were no differences between the refusers and the participants on a variety of demographic measures. The age range was from 29 to 52 years (mean = 41.86 years, SD = 6.4 years). The pairs came from throughout Sweden, with 19% from Stockholm, which is exactly the same proportion as in the general population. Serological analysis of 10 marker systems from serum, plasma, and red blood cells indicated that one DZT pair was actually MZT and one MZA pair was DZA. The latter pair was dropped from twin analysis. There were no Span data for one MZT pair. Thus, the final sample consisted of 9 MZA, 10 MZT, and 14 DZT pairs. The age at separation for the MZA twins ranged from 1 to 8 years, and 55% were separated before their first birthday. Earlier characterization of the SATSA reared-apart sample demonstrated that twins reared apart do not differ from twins reared together except for lower standard of living during childhood (Pedersen et al., 1984). Table 1 presents data on the subjects’educational and marital status. The occupational level of subjects was categorized by their education, experience, and level of responsibility. Two of the categories were (1) housewife (3%) and (2) work that does not require special education (8%). The other categories were work that requires (3) a certain amount of training (24%); (4) special training and apprenticeship (36%); (5) high school or vocational school (17%); (6) a university degree, e.g., B.A. (12%); and (7) decision-making, great responsibilities, or a high academic education (0%). Subjects were normally distributed across these categories.
Table 1. Demographic data for subjects (n = 66) Marital status Single
% 6
Educational level
%
Elementary school
35
Living with spouse
82
Secondary/vocational
33
Divorced
12
Junior college
20
Widowed
0
Colleqe/universitv
12
All subjects received a standard medical examination with routine laboratory tests. Two of the included subjects had a history of viral encephalitis, and one subject had a history of migraine headaches. Subjects were interviewed by a psychiatrist for history of psychiatric illness, current psychiatric status, and familial history of psychiatric disease. The psychiatric assessment used the Structured Clinical Interview for DSM-III-R, Nonpatient Version (SCID-NP) (Spitzer et al., 1986). The mother of one MZA pair had been psychotic. Span performance of these twins was within 1 SD from the mean. Current level of functioning was rated on the SCID-NP Axis V scale (Spitzer et al., 1986). The mean level of functioning was 8.75 points, out of a maximum of 9 points. None of the subjects reported a level of functioning
118 below 6 points. The presence of psychotic
symptoms was assessed according to the SCID-NP Psychotic Screening (Spitzer et al., 1986). Three subjects reported experiencing some psychotic symptom during their lifetimes; two of those were the twins, who had a psychotic mother. One additional subject reported the possible occurrence of a psychotic symptom. Procedures. Span of Apprehension test. An Apple IIE computer controlled the presentation of stimuli, recorded the subject’s response, and scored the results using a program (Asarnow and Betts, 1982) designed expressly for this purpose. Stimuli were presented for approximately 60 ms on a black and white cathode ray terminal (CRT; VIDEO 100) with a 240 X 200 mm screen. Stimuli were presented only when the subject was attending to the CRT and was ready to respond. Subjects were told that either a “T”or an “F”(never both) would be flashed on the screen along with 11 other letters. They were instructed to respond by using the dominant hand to press a pair of buttons clearly marked with “T” or “F.“They were told to guess when in doubt. This forced choice procedure eliminates variance due to differences across subjects
in response bias. Subjects were given 96 experimental trials. The dependent variable was the number of correct detections. IQ was estimated using a Swedish test, the SRB (Dureman and Silde, 1959), which consists of the following three subtests: Synonyms, Reasoning, and Koh’s Block test. In the 30-item Synonyms subtest, a synonym to a target word has to be chosen from five alternatives presented for each item. The score is the number of correct responses. The 30-item Reasoning subtest was described by Thurstone (1941). For each item, five geometrical figures are given and the task is to indicate the figure that is different in some respect from the other four figures. The score is the number of correct responses. Koh’s Block test is a subtest of the Wechsler-Bellevue Intelligence Scales (Wechsler, 1939). Scores on the three subtests were summed, and a corresponding IQ value was read from the appropriate age group table. The Pearson product-moment correlation between the SRB and the Swedish version of the Wechsler-Bellevue Intelligence Scales is r = 0.804 (Dureman and SIlde, 1959). The correlations between the Wechsler-Bellevue Intelligence Scales and the SRB subscales are r = 0.78 for Synonyms, r = 0.64 for Reasoning, and r = 0.58 for the Block test.
Results Table 2 presents the means and standard deviations for the SRB and Span of Apprehension scores for the three groups of twins. The mean values for the two scores for all three groups were within normal values for the general population. There were no mean differences among the three groups of twins, but the MZA twins had significantly higher standard deviations than the MZT twins. The restricted variation in the MZT group may have resulted in depressed correlations for that group and may worsen the fit of behavioral-genetic models. The relative importance of genetic effects for phenotypic variation (heritability) may be estimated by taking twice the difference between the intraclass correlations 1981). In this study, for the Span of (t) for MZ and DZ twins (Falconer, Apprehension test, MZT correlations were more than twice the magnitude of DZT correlations (tMZT = 0.53, tDZT = -0.06), suggesting that genetic effects were operating nonadditively. Intraclass correlations were significant for the MZA and MZT twins for both measures, but not for the DZ twins. In the presence of nonadditive effects, heritability derived in this manner will be overestimated (hz = 1.18). Alternatively, the intraclass correlation of MZA twins represents the single best estimate of heritability unbiased by possible effects of shared rearing environment.
119
Table 2. Means and standard deviations for IQ and number of correct responses for Span of Apprehension test WZA (n = 18)
Mean IQ Span of Apprehension
106.3
67.2
DZT (n = 28)
(n!%) SD
15.3
10.4
Mean 112.3
68.6
SD 7.3
6.0
Mean 106.1
88.7
SD 13.9
8.2
Note. Mi?A = monozygotic twins reared apart MTT = monozygotic twins reared together. DZT = dizygotic twins reared together.
For the Span of Apprehension, the MZA correlation was 0.74, suggesting that a more realistic estimate of the importance of genetic effects is around 70% of the variation. Nonshared environmental factors unique to the individual account for the remaining approximately 30% of the variation. For IQ, the MZT correlation was 0.57, the DZT correlation was 0.30, and the MZA correlation was 0.94. The two estimates of heritability are therefore 0.54 and 0.94. One of the primary reasons for studying twins reared apart is to assess the importance of sharing the same rearing environment to similarity in twins later in life, If twins reared together are more similar than twins reared apart, shared rearing environment is of importance. In the present study, correlations for twins reared apart were not smaller than those for twins reared together, indicating that sharing the same rearing environment does not contribute to twin similarity in performance on the Span of Apprehension test. For IQ, and to some extent for Span of Apprehension performance, MZA correlations are greater than MZT correlations. If replicated, this pattern of correlations would provide evidence for sibling competition whereby twins reared together strive to be different from each other. Model-fitting analyses that use the information from all three groups of twins simultaneously represent a more powerful method to estimate the importance of genetic and environmental parameters. In addition, standard errors of estimates and measures of goodness of fit are provided. Significance of parameters can also be tested by comparing the fit of reduced models from which parameters are dropped or fixed to zero. A significant change in the ~2 indicates that the parameter was important. A detailed description of the application of these techniques to the study of twins reared apart has been presented elsewhere (Jinks and Fulker, 1970; Pedersen et al., 1988). Observed and expected mean squares were entered into LISREL VI program (Jdreskog and S&born, 1986) which was used to estimate the square roots of the genetic and environmental variances. Table 3 presents the results from model-fitting analyses. A satisfactory fit was obtained for both Span of Apprehension and IQ. Shared environmental parameters were not significant for either measure in the first model. Removal of the genetic parameter from the model resulted in a significant worsening of fit, indicating that genetic variance is important for both measures. There was not adequate power to determine whether nonadditive genetic variance was important. Recomputation of the parameters as percentages of total variance confirmed heritability estimates from
120 comparison of correlations: heritability was 0.7 1 for the Span of Apprehension, and 0.86 for IQ. The remaining variance (0.29 and 0.14, respectively) was attributable to environmental variance not shared by family members.
Table 3. Parameter estimates and SE for genetic and nonshared environmental parameters Parameterestimates Variable Span
Model
Apprehension
1
0.892 zto.145
2
IQ
X2
df
P
-
5.74
4
0.219
0.812
0.619
10.99
4
0.027
Iko.105
+0.171
4.78
3
0.188
13.98
4
0.007
Ens
G
EC
of
(1)
-
0.976 +0.251
(2)
-
0.574 Ito.
0
0.392 f0.067 0.642
0.800
f0.083
10.148
Note. Parameter estimates are the square roots of the variances
These univariate analyses indicate substantial genetic variation for the Span of Apprehension and for IQ. However, the two measures are quite highly correlated (r = 0.52). The next logical question is whether these two measures are influenced by some common genetic factor(s), or whether the genetic effects that are important for the Span of Apprehension are different from those that are important for IQ. In other words, to what extent is the covariation between Span of Apprehension and IQ due to common genetic and environmental effects? To answer this question, a multivariate behavioral genetic model was applied to the mean squares and cross-products (Martin and Eaves, 1977; Fulker et al., 1983; Boomsma and Molenaar, 1986). The model depicted in Fig. 1 includes a genetic factor (G,) and a nonshared environmental factor (E,,_,) that loads on both Span of Apprehension and IQ.
1. Path model of loadings on common and unique genetic, and common and unique nonshared environmental factors for Span of Apprehension and IQ
Fig.
2x3 =u
G, = common genetic factors. G, = unique genetic factors. En,., En,_, = unique nonshared environmental factors.
Ens-u
= common
nonshared
environmental
factors.
121 Because a Cholesky decomposition was used, unique genetic (G,) and unique nonshared environmental (E,,_,) factors loading only on the Span of Apprehension were also included. In this model, one can estimate the relative importance of genetic and environmental effects common to the Span of Apprehension and IQ, as well as the importance of other genetic and environmental effects that are only of importance to the Span of Apprehension. For a detailed discussion of the model and analytic procedures, see Boomsma and Molenaar (1986). Table 4 presents the parameter estimates and their standard errors. A goodness of fit test indicated that the model fits the data satisfactorily k* = 10.62, df = 12, p = 0.614). All of the nonzero parameters were significant except the loadings on the Table 4. Parameter estimates and SE for common (G,) and unique (G,) genetic, and common (EnsJ and unique (E,,.,) nonshared environmental factors Variable IQ
GC
GU
0.970
0.636 zto.15
EW”
0.400
Iko.13 Span of Apprehension
Ens-c *0.07
0.547 +0.15
0.00’
0.619 zto.10
1. This parameter was not significant in the expanded model and therefore set to zero
common nonshared environments factor (removal of this parameter resulted in a x2 of 10.74, df = 13, p = 0.633). Table 5 shows the proportions of variation explained by the various parameters. Consistent with the univariate results based on the correlations, heritability (total genetic variation) is 0.65 for the Span of Apprehension and 0.85 for IQ. Of the total variation for the Span of Apprehension, 37% is genetic variation shared with IQ, while 28% is genetic variation unique to the Span of Apprehension. Nonshared environmental influences account for 35% of the variation in the Span of Apprehension and 15% of the variation in IQ, and are unique to the two Table 5. Variance (%) explained by common (G,) and unique (G,) genetic, and common (En& and unique (E,+“) nonshared environmental factors Variable Ens-u GC G” Ens-c IQ 85 15 Span of Apprehension
37
28
35
measures, respectively. Another way of describing the results is the phenotypic correlation-that is, the extent to which genetic and environmental factors account for the associations among the measures. In this common factor model, the phenotypic correlation is due entirely to the genetic factor, since the path from the common “nonshared environmental factor” to the Span of Apprehension is 0.
122
Discussion Twin studies provide a powerful tool for assessing the importance of genetic factors in the etiology of diseases for which the actual genetic markers at the molecular level have not yet been identified. In schizophrenia research, the Span of Apprehension test has shown promise as a vulnerability marker (Asarnow et al., in press). Estimation of the relative importance of genetic factors (heritability) for this cognitive task in the general population represents a first step toward understanding the mechanisms underlying the performance of high risk populations. The main finding of the present study is that performance on the Span of Apprehension test in a representative sample of MZ and DZ twins appears to have a strong genetic component that accounts for approximately 70% of the total variation in performance on the Span of Apprehension test. The intraclass correlations for both MZ twins reared apart and MZ twins reared together are more than twice the magnitude of the DZ intraclass correlations. If replicated, this finding suggests that the genetic variance may be nonadditive-that is, that there are interactions between or within loci. If the genetic variance is nonadditive, heritability estimates from parent-offspring designs will be lower than those from twin studies. To date, however, parent-offspring designs have focused on mean levels of performance in children at risk instead of assessing the degree of similarity in first degree relatives. Contrary to the findings in schizophrenic probands, results on the Span of Apprehension and IQ are substantially correlated in this normal population (r = 0.52). The next question asked was whether these two characteristics were influenced by the same genetic or environmental factors. Multivariate behavioral-genetic analyses indicated that slightly less than half of the genetic effects important to the Span of Apprehension are unique to it, while the remaining genetic effects may be the same as those that influence IQ. Furthermore, the phenotypic correlation between performance on the Span of Apprehension test and the IQ score may be entirely attributed to common genetic mechanisms. Future studies with Span of Apprehension and IQ in families of schizophrenic probands will be necessary to determine whether the mechanisms responsible for the relationship between Span of Apprehension and IQ or Span of Apprehension and schizophrenia are the same. The results of the present study suggest that in the normal population individual differences in performance on the Span of Apprehension test (in the absence of acquired CNS insults) are in part genetically determined. Performance on the Span of Apprehension test was found to be impaired in about 40% of schizophrenic patients as opposed to other psychiatric groups (Asarnow and MacCrimmon, 1982), and impaired performance is also present in remission. The measure was found to be sensitive to neuroleptic treatment effects (Spohn et al., 1977, 1985) and to detect deficits in foster-reared children of schizophrenic biological mothers (Asarnow et al., 1977) and in the nonpsychotic mothers of schizophrenic patients (Wagener et al., 1986). Taken collectively, these findings indicate that performance on the Span of Apprehension test, which may be an index of vulnerability to schizophrenia, is largely influenced by genetic effects. Furthermore, these effects are not shared with IQ. Although these data are descriptive of the normal population, they do not allow
123
us to generalize to schizophrenic subjects. Replicating the results of the current study in samples of schizophrenic twins would provide a rigorous test of the hypothesis that the Span of Apprehension test taps aspects of the genetic liability to schizophrenic disorder. Designing future twin studies so that each of the multiple cognitive functions tapped by the Span of Apprehension test can be individually assessed should help identify the unique genetic component of performance on the test. Acknowledgment. This study was supported by grants from the Bank of Sweden Tercentenary Fund, the Swedish Medical Research Council (4545), and funds from the Karolinska Institute. The authors thank Birgitta Axelsson, M.D., and Peter Nordstrom, M.D., for performing the psychiatric interviews.
References Asarnow, J.R. Children at risk for schizophrenia: Converging lines of evidence. Schizophrenia Bulletin, 14:613-631, 1988. Asarnow, R.F. The search for the biological substrate of schizophrenia: A perspective from studies of children at risk for schizophrenia. In: Tarder, R., ed. The Childat Psychiatric Risk. New York: Oxford University Press, 1983. pp. 150-194. Asarnow, R.F., and Bet& I.Q. Apple program for the Span of Apprehension. Unpublished test, 1982. Asarnow, R.F.; Granholm, E.; and Sherman, T. Span of Apprehension in schizophrenia. In: Steinhauer, S.; Gruzelier, J.H.; and Zubin, J., eds. Handbook of Schizophrenia: Neuropsychology, Psychophysiology and Information Processing. Vol. 4. Amsterdam: Elsevier Science Publishers, in press. Asarnow, R.F., and MacCrimmon, D.J. Attention, information processing, neuropsychological functioning, and thought disorder during the acute and partial recovery phases of schizophrenia: A longitudinal study. Psychiatry Research, 1:309-319, 1982. Asarnow, R.F.; Steffy, R.A.; MacCrimmon, D.J.; and Cleghorn, J.M. An attentional assessment of foster children at risk for schizophrenia. Journal of Abnormal Psychology, 86:267-275,1977. Boomsma, D.I., and Molenaar, P.C.M. Using LISREL to analyze genetic and environmental covariance structure. Behavior Genetics, 16:237-250, 1986. Dureman, I., and Salde, H. Psykometriska och experimentalpsykologiska metoder fur klinisk tilhimpning. Stockholm: Almquist & Wiksell, 1959. Estes, W.K., and Taylor, H.A. Visual detection in relation to display size and redundancy of critical elements. Perception and Psychophysics, 1:9, 1966. Falconer, D.S. Introduction to Quantitative Genetics. 2nd ed. New York: Longman, 1981. Fulker, D.W.; Baker, L.A.; and Bock, I.D. Estimating components of covariance using LISREL. Data Analyst, 15-8, 1983. Gottesman, I.I., and Shields, J. Schizophrenia: The Epigenetic Puzzle. Cambridge: Cambridge Universitv Press. 1982. Holzm&, P.S. Recent studies of psychophysiology in schizophrenia. Schizophrenia Bulletin. 13~49-75. 1987. Jinks; J.L., and Fulker, D.W. Comparison of the biometrical, genetical, MAVA, and classical approaches to the analysis of human behavior. Psychological Bulletin, 73:3 1 l-349, 1970. Joreskog, K.G., and SBrbom, D. LISREL VI: Analysis of Linear Structural Relationships by the Method of Maximum Likelihood. Morrisville, IN: Scientific Software, Inc., 1986. Kendler, K.S. Familial aggregation of schizophrenia and schizophrenia spectrum disorders: Evaluation of conflicting results. Archives of General Psychiatry, 45:377-383, 1988. Martin, N.G., and Eaves, L.J. The genetical analysis of covariance structure. Heredity, 38:79-95, 1977.
124 McCleam, G.E.; Pedersen, N.L.; Plomin, R.; Nesselroade, J.R.; Friberg, L.; and DeFaire, U. Age and gender effects for individual differences in behavioral aging: The Swedish Adoption/Twin Study of Aging. Comprehensive Gerontology, in press. Nuechterlein, K.H., and Dawson, M.E. Information processing and attentional functioning in the developmental course of schizophrenic disorders. Schizophrenia Bulletin, 10:160-203, 1984. Pedersen, N.L.; Friberg, L.; Floderus-Myrhed, B.; McClearn, G.E.; and Plomin, R. Swedish early separated twins: Identification and characterization. Acta Geneticae Medicae et Gemellologiae, 33~243-250, 1984. Pedersen, N.L.; Plomin, R.; McCleam G.E.; and Friberg, L.T. Neuroticism, extraversion, and related traits in adult twins reared apart and together. Journal of Personality and Social Psychology, 55950-957, 1988. Plomin, R.; DeFries, J.C.; and McClearn, G.E. Behavior Genetics: A Primer. 2nd ed. New York: WH Freeman, 1989. Prescott, C.A.; Strauss, M.E.; and Tune, L.E. Test-test reliability of information-processing measures among chronic schizophrenics. To be published, 1991. Spitzer, R.L.; Williams, J.B.W.; and Gibbon, M. Structured Clinical Interview for DSM III-R-Non-Patient Version (SCZD-NP). New York: New York State Psychiatric Institute, 1986. Spohn, H.E.; Coyne, L.; Lacoursiere, R.B.; Mazur, D.; and Hayes, K. Relation of neuroleptic dose and tardive dyskinesia to attention, information processing and psychophysiology in medicated schizophrenics. Archives of General Psychiatry, 42:849-859, 1985. Spohn, H.E.; Lacoursiere, R.B.; Thompson, K.; and Coyne, Lacoursiere, R.B.; Mazur, D.; and Hayes, K. Relation of neuroleptic dose and tardive dyskinesia to attention, information processing and psychophysiology in medicated schizophrenics. Archives of General Psychiatry, 42:849-859, 1985. Spohn, H.E.; Lacoursiere, R.B.; Thompson, K.; and Coyne, L. Phenothiazine effects on psychological and psychophysiological dysfunction in chronic schizophrenics. Archives of General Psychiatry, 341633-644, 1977. and information processing as indicators of Spring, B.J., and Zubin, J. Attention vulnerability to schizophrenic episodes. Journal of Psychiatric Research, 14:289-302, 1978. span in Strauss, M.E.; Bohannon, W.E.; Stephens, J.H.; and Panzer, N.E. Perceptual schizophrenia and affective disorders. Journal of Nervous and Mental Disease, 172143 l-442, 1984. Thurstone, L.L. Primary mental abilities. Psychometric Monographs. Vol. 2. Chicago: University of Chicago Press, 1941. Vandenberg, S.G., and Vogler, G.P. Genetic determinants of intelligence. In: Wolman, B.B., ed. Handbook of Intelligence, Theories Measurements and Applications. New York: Wiley, 1985. pp 3-57. Wagener, D.K.; Hogarty, G.E.; Goldstein, M.J.; Asarnow, R.F.; and Browne, A. Information processing and communication deviance in schizophrenic patients and their mothers. Psychiatry Research, 18:365-377, 1986. Wechsler, D. The Measurement of Adult Intelligence. Baltimore: Williams & Wilkins Company, 1939.
Genetic Study
115
Factors for the Span of Apprehension of Normal Twins
Aniko Bartfai, Nancy L. Pedersen,
Robert F. Asarnow,
Test: A
and Daisy Schalling
Received March 22, 1990; revised version received November 26, 1990; accepted February 3, 1991. Abstract. The Partial Report Span of Apprehension test has been found to detect cognitive deficits in some first degree relatives of schizophrenic patients. TO assess
the relative contribution of genetic vs. environmental factors on this measure, 19 monozygotic and 14 dizygotic female twin pairs, selected from a normal population, were tested on the Span of Apprehension test and an IQ test. Both Span of Apprehension test performance and IQ score had high heritabilities: 0.65 and 0.7 1, respectively. The mode of transmission for performance on the Span of Apprehension test appears to operate in a nonadditive manner. A multivariate behavioral-genetic model applied to the Span of Apprehension and IQ measures indicated that slightly less than half of the genetic effects important for the Span of Apprehension test are found in common with the genetic factors important for IQ. The phenotypic correlation between the Span of Apprehension and IQ measures can be attributed entirely to genetic factors. The influence of unique genetic components in the performance of the Span of Apprehension test in the general population heightens the promise of this measure as a genetic marker for schizophrenia.
Key Words. Span of Apprehension,
vulnerability,
IQ, twin study, schizophrenia.
A critical step in elucidating the mechanism(s) for the transmission of schizophrenia is determining precisely what is transmitted. It is now generally accepted that schizophrenia is familially transmitted and that what is transmitted extends beyond psychotic symptoms, also including certain personality disorders. The precise phenotype for the schizophrenic disorders, however, has yet to be clearly defined (Gottesman and Shields, 1982; Kendler, 1988). The lack of a clear definition has stimulated efforts to find sensitive measures of schizophrenic phenotype(s). One promising area of investigation focuses on information processing tasks that are thought to tap the subtle central nervous system (CNS) defects hypothesized to underlie schizophrenic symptoms. A number of information processing tasks that
Aniko Bartfai, Ph.D., is Senior Lecturer, Department of Psychology,
Stockholm University, and Researcher, Department of Psychiatry and Psychology, Karolinska Institute, Stockholm, Sweden. Nancy L. Pedersen, Ph.D., is Associate Professor, Department of Environmental Hygiene, Karolinska Institute, Stockholm, Sweden. Robert F. Asarnow, Ph.D., is Professor, Department of Psychiatry, Neuropsychiatric Institute, UCLA School of Medicine, Los Angeles, CA, USA. Daisy Schalling, Ph.D., is Professor, Department of Psychology, Stockholm University, and Department of Psychiatry and Psychology, Karolinska Institute, Stockholm, Sweden. (Reprint requests to Dr. A. Bartfai, Dept. of Psychiatry and Psychology, Karolinska Hospital, 104 01 Stockholm, Sweden.) 0165-1781191
jSO3.50 @ 1991 Elsevier Scientific
Publishers
Ireland
Ltd.
116 require rapid processing of information have detected dysfunctions in nonpsychotic first degree relatives of schizophrenic probands (for reviews, see R.F. Asarnow, 1983; Nuechterlein and Dawson, 1984; Holzman, 1987; J.R. Asarnow, 1988). One particularly promising task is the Partial Report Span of Apprehension test (Estes and Taylor, 1966), which measures the amount of information extracted from briefly presented visual displays. While the results of a few studies (e.g., Strauss et al., 1984; Prescott et al., 1991) cast doubt upon the specificity of deficits in performance on the Span of Apprehension test to schizophrenia, a recent review (Asarnow et al., in press) reveals that (1) seven of eight studies found that schizophrenic patients performed significantly worse than normal subjects, and (2) three of four studies found significant differences between schizophrenic patients and psychiatric contrast groups. Both foster-reared children whose biological mothers were schizophrenic (Asarnow et al., 1977) and the nonpsychotic mothers of schizophrenic probands (Wagener et al., 1986) also show deficits in this task. The current data, with some few exceptions, suggest that the Span of Apprehension test may meet Spring and Zubin’s (1978) criteria for measures of the genetic liability to schizophrenic disorder. According to Spring and Zubin, such a measure should detect deficits in individuals generally at risk but not necessarily schizophrenic, and should show concordance among ill schizophrenic patients, their healthy siblings, and schizophrenic patients in remission. While the presence of information processing impairments in the first degree relatives of schizophrenic probands is consistent with the hypothesis that the Span of Apprehension test may be a sensitive measure of the schizophrenic phenotype, familial aggregation does not necessarily demonstrate genetic transmission. Shared environmental factors could also be involved. One powerful method to separate shared familial environments from genetic effects is the comparison of monozygotic twins reared together with those reared apart (Gottesman and Shields, 1982). To our knowledge, this method has not yet been applied to the Span of Apprehension test. The present study compared the similarity between the Span of Apprehension performance of normal monozygotic and dizygotic twins reared together and monozygotic twins reared apart to determine the extent to which individual differences in Span of Apprehension performance in normal subjects are heritable. Scores on the Span of Apprehension test are not highly correlated with estimates of IQ in schizophrenic probands (Asarnow et al., in press), but the presence of an association in a normal population has not yet been examined. If a strong association were found, it would indicate that the Span of Apprehension test is simply tapping the abilities summarized by IQ, and thus would diminish its possible importance as an independent marker of vulnerability. One purpose of the present study was to determine the extent of the correlation between Span of Apprehension and IQ measures in a normal population. A number of cognitive abilities are heritable in the general population (Vandenberg and Vogler, 1985), including the broad set of abilities indexed by tests of general intellectual ability (IQ). An analysis of the genetic effects for the Span of Apprehension test uncorrected for IQ could in part reflect genetic effects for IQ. The present study, therefore, attempted to assess the total importance of genetic effects for Span of Apprehension performance, as well as genetic effects unique to the task, that are independent of IQ.
117
Methods Subjects. The subjects were drawn from the ongoing Swedish Adoption/Twin Study of Aging (SATSA; for details, see Pedersen et al., 1984, 1988; McClearn et al., in press), which includes all twins from the population based Swedish Twin Register who were separated at an early age and reared apart and a matched sample of twins reared together. All female pairs under 50 years of age in which both members responded to a mailout questionnaire in 1984 were considered for participation. Pairs were contacted on a random basis until the quota of 10 pairs of monozygotic twins reared apart (MZA), 10 pairs of monozygotic twins reared together (MZT), and 15 pairs of dizygotic twins reared together (DZT) was met. At this point, a preliminary zygosity diagnosis was based on responses to questionnaire items concerning physical similarity. Subjects were contacted by letter and later by phone by a research assistant, who informed them about the purpose of the study and explained procedures. Only pairs in which both twins were willing to participate were brought into a central testing location at the Karolinska Hospital in Stockholm. The refusal rate was 31%. Reasons for refusal include not being able to leave jobs (shop owners), no help in taking care of small children, and the inconvenience of traveling to Stockholm. Only three subjects refused because of lack of interest. There were no differences between the refusers and the participants on a variety of demographic measures. The age range was from 29 to 52 years (mean = 41.86 years, SD = 6.4 years). The pairs came from throughout Sweden, with 19% from Stockholm, which is exactly the same proportion as in the general population. Serological analysis of 10 marker systems from serum, plasma, and red blood cells indicated that one DZT pair was actually MZT and one MZA pair was DZA. The latter pair was dropped from twin analysis. There were no Span data for one MZT pair. Thus, the final sample consisted of 9 MZA, 10 MZT, and 14 DZT pairs. The age at separation for the MZA twins ranged from 1 to 8 years, and 55% were separated before their first birthday. Earlier characterization of the SATSA reared-apart sample demonstrated that twins reared apart do not differ from twins reared together except for lower standard of living during childhood (Pedersen et al., 1984). Table 1 presents data on the subjects’educational and marital status. The occupational level of subjects was categorized by their education, experience, and level of responsibility. Two of the categories were (1) housewife (3%) and (2) work that does not require special education (8%). The other categories were work that requires (3) a certain amount of training (24%); (4) special training and apprenticeship (36%); (5) high school or vocational school (17%); (6) a university degree, e.g., B.A. (12%); and (7) decision-making, great responsibilities, or a high academic education (0%). Subjects were normally distributed across these categories.
Table 1. Demographic data for subjects (n = 66) Marital status Single
% 6
Educational level
%
Elementary school
35
Living with spouse
82
Secondary/vocational
33
Divorced
12
Junior college
20
Widowed
0
Colleqe/universitv
12
All subjects received a standard medical examination with routine laboratory tests. Two of the included subjects had a history of viral encephalitis, and one subject had a history of migraine headaches. Subjects were interviewed by a psychiatrist for history of psychiatric illness, current psychiatric status, and familial history of psychiatric disease. The psychiatric assessment used the Structured Clinical Interview for DSM-III-R, Nonpatient Version (SCID-NP) (Spitzer et al., 1986). The mother of one MZA pair had been psychotic. Span performance of these twins was within 1 SD from the mean. Current level of functioning was rated on the SCID-NP Axis V scale (Spitzer et al., 1986). The mean level of functioning was 8.75 points, out of a maximum of 9 points. None of the subjects reported a level of functioning
118 below 6 points. The presence of psychotic
symptoms was assessed according to the SCID-NP Psychotic Screening (Spitzer et al., 1986). Three subjects reported experiencing some psychotic symptom during their lifetimes; two of those were the twins, who had a psychotic mother. One additional subject reported the possible occurrence of a psychotic symptom. Procedures. Span of Apprehension test. An Apple IIE computer controlled the presentation of stimuli, recorded the subject’s response, and scored the results using a program (Asarnow and Betts, 1982) designed expressly for this purpose. Stimuli were presented for approximately 60 ms on a black and white cathode ray terminal (CRT; VIDEO 100) with a 240 X 200 mm screen. Stimuli were presented only when the subject was attending to the CRT and was ready to respond. Subjects were told that either a “T”or an “F”(never both) would be flashed on the screen along with 11 other letters. They were instructed to respond by using the dominant hand to press a pair of buttons clearly marked with “T” or “F.“They were told to guess when in doubt. This forced choice procedure eliminates variance due to differences across subjects
in response bias. Subjects were given 96 experimental trials. The dependent variable was the number of correct detections. IQ was estimated using a Swedish test, the SRB (Dureman and Silde, 1959), which consists of the following three subtests: Synonyms, Reasoning, and Koh’s Block test. In the 30-item Synonyms subtest, a synonym to a target word has to be chosen from five alternatives presented for each item. The score is the number of correct responses. The 30-item Reasoning subtest was described by Thurstone (1941). For each item, five geometrical figures are given and the task is to indicate the figure that is different in some respect from the other four figures. The score is the number of correct responses. Koh’s Block test is a subtest of the Wechsler-Bellevue Intelligence Scales (Wechsler, 1939). Scores on the three subtests were summed, and a corresponding IQ value was read from the appropriate age group table. The Pearson product-moment correlation between the SRB and the Swedish version of the Wechsler-Bellevue Intelligence Scales is r = 0.804 (Dureman and SIlde, 1959). The correlations between the Wechsler-Bellevue Intelligence Scales and the SRB subscales are r = 0.78 for Synonyms, r = 0.64 for Reasoning, and r = 0.58 for the Block test.
Results Table 2 presents the means and standard deviations for the SRB and Span of Apprehension scores for the three groups of twins. The mean values for the two scores for all three groups were within normal values for the general population. There were no mean differences among the three groups of twins, but the MZA twins had significantly higher standard deviations than the MZT twins. The restricted variation in the MZT group may have resulted in depressed correlations for that group and may worsen the fit of behavioral-genetic models. The relative importance of genetic effects for phenotypic variation (heritability) may be estimated by taking twice the difference between the intraclass correlations 1981). In this study, for the Span of (t) for MZ and DZ twins (Falconer, Apprehension test, MZT correlations were more than twice the magnitude of DZT correlations (tMZT = 0.53, tDZT = -0.06), suggesting that genetic effects were operating nonadditively. Intraclass correlations were significant for the MZA and MZT twins for both measures, but not for the DZ twins. In the presence of nonadditive effects, heritability derived in this manner will be overestimated (hz = 1.18). Alternatively, the intraclass correlation of MZA twins represents the single best estimate of heritability unbiased by possible effects of shared rearing environment.
119
Table 2. Means and standard deviations for IQ and number of correct responses for Span of Apprehension test WZA (n = 18)
Mean IQ Span of Apprehension
106.3
67.2
DZT (n = 28)
(n!%) SD
15.3
10.4
Mean 112.3
68.6
SD 7.3
6.0
Mean 106.1
88.7
SD 13.9
8.2
Note. Mi?A = monozygotic twins reared apart MTT = monozygotic twins reared together. DZT = dizygotic twins reared together.
For the Span of Apprehension, the MZA correlation was 0.74, suggesting that a more realistic estimate of the importance of genetic effects is around 70% of the variation. Nonshared environmental factors unique to the individual account for the remaining approximately 30% of the variation. For IQ, the MZT correlation was 0.57, the DZT correlation was 0.30, and the MZA correlation was 0.94. The two estimates of heritability are therefore 0.54 and 0.94. One of the primary reasons for studying twins reared apart is to assess the importance of sharing the same rearing environment to similarity in twins later in life, If twins reared together are more similar than twins reared apart, shared rearing environment is of importance. In the present study, correlations for twins reared apart were not smaller than those for twins reared together, indicating that sharing the same rearing environment does not contribute to twin similarity in performance on the Span of Apprehension test. For IQ, and to some extent for Span of Apprehension performance, MZA correlations are greater than MZT correlations. If replicated, this pattern of correlations would provide evidence for sibling competition whereby twins reared together strive to be different from each other. Model-fitting analyses that use the information from all three groups of twins simultaneously represent a more powerful method to estimate the importance of genetic and environmental parameters. In addition, standard errors of estimates and measures of goodness of fit are provided. Significance of parameters can also be tested by comparing the fit of reduced models from which parameters are dropped or fixed to zero. A significant change in the ~2 indicates that the parameter was important. A detailed description of the application of these techniques to the study of twins reared apart has been presented elsewhere (Jinks and Fulker, 1970; Pedersen et al., 1988). Observed and expected mean squares were entered into LISREL VI program (Jdreskog and S&born, 1986) which was used to estimate the square roots of the genetic and environmental variances. Table 3 presents the results from model-fitting analyses. A satisfactory fit was obtained for both Span of Apprehension and IQ. Shared environmental parameters were not significant for either measure in the first model. Removal of the genetic parameter from the model resulted in a significant worsening of fit, indicating that genetic variance is important for both measures. There was not adequate power to determine whether nonadditive genetic variance was important. Recomputation of the parameters as percentages of total variance confirmed heritability estimates from
120 comparison of correlations: heritability was 0.7 1 for the Span of Apprehension, and 0.86 for IQ. The remaining variance (0.29 and 0.14, respectively) was attributable to environmental variance not shared by family members.
Table 3. Parameter estimates and SE for genetic and nonshared environmental parameters Parameterestimates Variable Span
Model
Apprehension
1
0.892 zto.145
2
IQ
X2
df
P
-
5.74
4
0.219
0.812
0.619
10.99
4
0.027
Iko.105
+0.171
4.78
3
0.188
13.98
4
0.007
Ens
G
EC
of
(1)
-
0.976 +0.251
(2)
-
0.574 Ito.
0
0.392 f0.067 0.642
0.800
f0.083
10.148
Note. Parameter estimates are the square roots of the variances
These univariate analyses indicate substantial genetic variation for the Span of Apprehension and for IQ. However, the two measures are quite highly correlated (r = 0.52). The next logical question is whether these two measures are influenced by some common genetic factor(s), or whether the genetic effects that are important for the Span of Apprehension are different from those that are important for IQ. In other words, to what extent is the covariation between Span of Apprehension and IQ due to common genetic and environmental effects? To answer this question, a multivariate behavioral genetic model was applied to the mean squares and cross-products (Martin and Eaves, 1977; Fulker et al., 1983; Boomsma and Molenaar, 1986). The model depicted in Fig. 1 includes a genetic factor (G,) and a nonshared environmental factor (E,,_,) that loads on both Span of Apprehension and IQ.
1. Path model of loadings on common and unique genetic, and common and unique nonshared environmental factors for Span of Apprehension and IQ
Fig.
2x3 =u
G, = common genetic factors. G, = unique genetic factors. En,., En,_, = unique nonshared environmental factors.
Ens-u
= common
nonshared
environmental
factors.
121 Because a Cholesky decomposition was used, unique genetic (G,) and unique nonshared environmental (E,,_,) factors loading only on the Span of Apprehension were also included. In this model, one can estimate the relative importance of genetic and environmental effects common to the Span of Apprehension and IQ, as well as the importance of other genetic and environmental effects that are only of importance to the Span of Apprehension. For a detailed discussion of the model and analytic procedures, see Boomsma and Molenaar (1986). Table 4 presents the parameter estimates and their standard errors. A goodness of fit test indicated that the model fits the data satisfactorily k* = 10.62, df = 12, p = 0.614). All of the nonzero parameters were significant except the loadings on the Table 4. Parameter estimates and SE for common (G,) and unique (G,) genetic, and common (EnsJ and unique (E,,.,) nonshared environmental factors Variable IQ
GC
GU
0.970
0.636 zto.15
EW”
0.400
Iko.13 Span of Apprehension
Ens-c *0.07
0.547 +0.15
0.00’
0.619 zto.10
1. This parameter was not significant in the expanded model and therefore set to zero
common nonshared environments factor (removal of this parameter resulted in a x2 of 10.74, df = 13, p = 0.633). Table 5 shows the proportions of variation explained by the various parameters. Consistent with the univariate results based on the correlations, heritability (total genetic variation) is 0.65 for the Span of Apprehension and 0.85 for IQ. Of the total variation for the Span of Apprehension, 37% is genetic variation shared with IQ, while 28% is genetic variation unique to the Span of Apprehension. Nonshared environmental influences account for 35% of the variation in the Span of Apprehension and 15% of the variation in IQ, and are unique to the two Table 5. Variance (%) explained by common (G,) and unique (G,) genetic, and common (En& and unique (E,+“) nonshared environmental factors Variable Ens-u GC G” Ens-c IQ 85 15 Span of Apprehension
37
28
35
measures, respectively. Another way of describing the results is the phenotypic correlation-that is, the extent to which genetic and environmental factors account for the associations among the measures. In this common factor model, the phenotypic correlation is due entirely to the genetic factor, since the path from the common “nonshared environmental factor” to the Span of Apprehension is 0.
122
Discussion Twin studies provide a powerful tool for assessing the importance of genetic factors in the etiology of diseases for which the actual genetic markers at the molecular level have not yet been identified. In schizophrenia research, the Span of Apprehension test has shown promise as a vulnerability marker (Asarnow et al., in press). Estimation of the relative importance of genetic factors (heritability) for this cognitive task in the general population represents a first step toward understanding the mechanisms underlying the performance of high risk populations. The main finding of the present study is that performance on the Span of Apprehension test in a representative sample of MZ and DZ twins appears to have a strong genetic component that accounts for approximately 70% of the total variation in performance on the Span of Apprehension test. The intraclass correlations for both MZ twins reared apart and MZ twins reared together are more than twice the magnitude of the DZ intraclass correlations. If replicated, this finding suggests that the genetic variance may be nonadditive-that is, that there are interactions between or within loci. If the genetic variance is nonadditive, heritability estimates from parent-offspring designs will be lower than those from twin studies. To date, however, parent-offspring designs have focused on mean levels of performance in children at risk instead of assessing the degree of similarity in first degree relatives. Contrary to the findings in schizophrenic probands, results on the Span of Apprehension and IQ are substantially correlated in this normal population (r = 0.52). The next question asked was whether these two characteristics were influenced by the same genetic or environmental factors. Multivariate behavioral-genetic analyses indicated that slightly less than half of the genetic effects important to the Span of Apprehension are unique to it, while the remaining genetic effects may be the same as those that influence IQ. Furthermore, the phenotypic correlation between performance on the Span of Apprehension test and the IQ score may be entirely attributed to common genetic mechanisms. Future studies with Span of Apprehension and IQ in families of schizophrenic probands will be necessary to determine whether the mechanisms responsible for the relationship between Span of Apprehension and IQ or Span of Apprehension and schizophrenia are the same. The results of the present study suggest that in the normal population individual differences in performance on the Span of Apprehension test (in the absence of acquired CNS insults) are in part genetically determined. Performance on the Span of Apprehension test was found to be impaired in about 40% of schizophrenic patients as opposed to other psychiatric groups (Asarnow and MacCrimmon, 1982), and impaired performance is also present in remission. The measure was found to be sensitive to neuroleptic treatment effects (Spohn et al., 1977, 1985) and to detect deficits in foster-reared children of schizophrenic biological mothers (Asarnow et al., 1977) and in the nonpsychotic mothers of schizophrenic patients (Wagener et al., 1986). Taken collectively, these findings indicate that performance on the Span of Apprehension test, which may be an index of vulnerability to schizophrenia, is largely influenced by genetic effects. Furthermore, these effects are not shared with IQ. Although these data are descriptive of the normal population, they do not allow
123
us to generalize to schizophrenic subjects. Replicating the results of the current study in samples of schizophrenic twins would provide a rigorous test of the hypothesis that the Span of Apprehension test taps aspects of the genetic liability to schizophrenic disorder. Designing future twin studies so that each of the multiple cognitive functions tapped by the Span of Apprehension test can be individually assessed should help identify the unique genetic component of performance on the test. Acknowledgment. This study was supported by grants from the Bank of Sweden Tercentenary Fund, the Swedish Medical Research Council (4545), and funds from the Karolinska Institute. The authors thank Birgitta Axelsson, M.D., and Peter Nordstrom, M.D., for performing the psychiatric interviews.
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