A Prospective Cohort Study of Childhood Behavioral Deviance and Language Abnormalities as Predictors...

A Prospective Cohort Study of ChildhoodBehavioral Deviance and Language Abnormalities

as Predictors of Adult Schizophreniaby Carrie E. Bearden, Isabelle M. Rosso, J. Megginson HoUister,

Laura E. Sanchez, Trevor Hadley, and Tyrone D. Cannon

Abstract

Language and behavioral deviance in early child-hood in preschizophrenia individuals suggests thatthe pathologic processes predisposing to schizophre-nia are present from early in life. However, the etio-logic antecedents of such impairments, and thedegree to which they predict adult schizophrenia,have not been conclusively demonstrated. To addressthis, we examined language and behavioral predic-tors of adult psychiatric outcome in a populationcohort (72 individuals with schizophrenia orschizoaffective disorder, 63 of their unaffected sib-lings, and 7,941 with no diagnosis) evaluatedprospectively with behavioral examinations and aspeech and language evaluation at 8 months, 4 years,and 7 years of age. Psychiatric outcome was ascer-tained via adult treatment contacts, and diagnoseswere made by chart review according to DSM-IVcriteria. Social maladjustment at age 7 was found topredict adult schizophrenia, and focal deviantbehaviors (e.g., echolalia, meaningless laughter) atages 4 and 7 were significantly associated with bothschizophrenia and sibling status. Unintelligiblespeech at age 7 was a highly significant predictor ofadult schizophrenia (odds ratio = 12.7), and poorexpressive language ability predicted both schizo-phrenia and unaffected sibling outcome. Earlybehavioral and language dysfunction did not differ-entially characterize preschizophrenia subjects witha history of fetal hypoxia or an early age of firsttreatment contact. Given that unaffected siblingsshow similar signs of deviance, such problems mayindicate genotypic susceptibility to the disorder, orshared environmental influences, or both.

Keywords: Schizophrenia, premorbid behavior,language, risk factors.

Schizophrenia Bulletin, 26(2):395-410,2000.

Abnormalities of behavior and language represent funda-mental aspects of schizophrenic illness (e.g., Bleuler 1911;Kraepelin 1919). The fact that more subtle disturbances ofsocial behavior and communication often exist longbefore the onset of psychosis suggests that the pathologicprocesses predisposing to schizophrenia may be pres-ent at least to some degree from very early in life. Alsoconsistent with this interpretation is evidence from neu-ropathology studies of schizophrenia of cytoarchitecturalchanges attributable to genetic and/or teratogenic distur-bances during gestation (Benes et al. 1986; Benes 1987;Conrad and Scheibel 1987; Arnold et al. 1991; Akbarian etal. 1993).

Retrospective and prospective cohort studies haveconsistently documented the existence of abnormalities inpremorbid social development in preschizophrenia indi-viduals (e.g., Hallett et al. 1986; Erlenmeyer-Kimling andCornblatt 1987; Cannon and Mednick 1993) ranging fromsolitary play preference at age 4 (Jones et al. 1994) tosocial anxiety, withdrawal, and acting-out behavior inadolescence (Weintraub 1987; Jones et al. 1994, 1995;Gupta et al. 1995). Preschizophrenia children are morelikely than normal children to be described by their teach-ers as "introverted," "disagreeable," and "emotionallyunstable" (Watt 1978). Similar findings have beenreported in high-risk studies, which indicate that offspringof parents with schizophrenia display a variety of behav-ioral problems, including acting-out problems, withdrawnbehavior, and attentional deficits (Weintraub 1987).However, because few of these high-risk samples havebeen followed up in adulthood, these studies have not yetdetermined that early social deficits predict an adult diag-nosis of schizophrenia. In addition, few studies haveaddressed the developmental time course of the emer-

Send reprint requests to Prof. T.D. Cannon, University of California,Los Angeles, Dept. of Psychology, 1285 Franz Hall, Box 951563, LosAngeles, CA 90095-1563; e-mail: [email protected].

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Schizophrenia Bulletin, Vol. 26, No. 2, 2000 C.E. Bearden et aL

gence of early signs of deviance. There is some sugges-tion that preschizophrenia subjects show increasingbehavioral deviance over the course of development (Watt1978; Neumann et al. 1995); unfortunately, both of thesestudies are limited by the lack of standard, prospectivelyadministered evaluations at each time point.

While developmental language delays and abnormali-ties are particularly salient in the histories of child and ado-lescent-onset schizophrenia subjects (e.g., Baltaxe andSimmons 1995), several studies offer evidence that abnor-malities of language exist many years before the onset of theadult form of schizophrenia (Green et al. 1984; Garralda1985; Jones et al. 1994). In a prospective longitudinal studyof a British birth cohort, Jones et al. (1994) found thatpreschizophrenia subjects attained speech milestones signif-icantly later than controls and had a higher frequency ofspeech problems between the ages of 2 and 15. WhileAmbelas (1992) also reported significantly higher rates ofdevelopmental problems in the area of speech, language,and reading in preschizophrenia children, Done et al. (1998)found that the written essays of children who later devel-oped schizophrenia did not differ from those of normal con-trol children. However, as these studies did not use formaltests to assess childhood language ability, the nature andextent to which specific areas of speech and language weredisturbed in early development remain to be elucidated.

Given that abnormalities of social-emotional behav-ior and language have been shown to exist in bothpreschizophrenia children prior to illness onset and theoffspring of parents with schizophrenia, these abnormali-ties do not appear to be a result of longstanding illness;rather, they appear to represent enduring markers of riskfor the disorder, possibly indicative of a genetic predispo-sition. Consistent with this interpretation are findings ofsimilar impairments in the unaffected first degree relativesof schizophrenia patients (Kinney et al. 1986; Baron andRisch 1987; Dumer et al. 1992). Although the existenceof childhood behavioral dysfunction in siblings of schizo-phrenia patients has not been formally investigated, anumber of studies have reported on elevated rates ofschizophrenia spectrum personality disorders, as well as"schizotypal" traits, including guardedness, suspicious-ness, and "magical thinking" in adult relatives of schizo-phrenia patients (Keefe et al. 1997; Chen et al. 1998;Kremen et al. 1998; Silverman et al. 1998). Further,impairments in language comprehension (Condray et al.1992) and some degree of reduced language complexity(Shedlack et al. 1997) have been reported in unaffectedadult relatives of schizophrenia patients, suggesting thatlanguage abnormalities may be an indicator of geneticvulnerability to the disorder.

Early childhood social and behavioral impairmentshave been reported to characterize only about one-third of

preschizophrenia individuals (Torrey et al. 1994;Neumann et al. 1995). Thus, it has been suggested thatthere is a distinct "neurodevelopmental" form of the dis-order, involving early language, behavioral, and neuromo-tor abnormalities, early onset, and poor prognosis thatmay stem from heterogeneity in etiologic factors (e.g.,obstetric complications [OCs]) (Lewis and Murray 1987;Murray and Lewis 1988; Foerster et al. 1991;O'Callaghan et al. 1991). In the Danish high-risk study, ahistory of OCs was present only among those schizophre-nia patients who displayed poor premorbid social adjust-ment and prominent negative symptoms (Cannon et al.1990). Thus, it is possible that the most poorly function-ing cases form a distinct category of severely affectedindividuals, and these cases account for the findings ofearly behavioral deviance and developmental delayamong preschizophrenia subjects overall. However, theuse of dichotomous outcome measures in many of thesestudies may have obscured the presence of more subtleimpairments in a larger percentage of preschizophreniasubjects, hi addition, in a companion report examiningOCs in relation to schizophrenia outcome in the cohortused in this study, a history of fetal hypoxia predictedschizophrenia, but other OCs did not (see Cannon et al.20006, in this issue). Thus, it seems likely that in thiscohort, hypoxic-ischemic brain damage in particular maybe the critical variable that distinguishes those showingbehavior deviance from those who do not

The aims of the present study were to determine therelationship of behavioral and language abnormalities inearly childhood to adult psychiatric outcome, and toexamine the combined and independent contributions ofgenetic and obstetric factors to such early signs of dys-function. Accordingly, we examined behavioral and lan-guage functioning at 8 months, 4 years, and 7 years of agein preschizophrenia children, their unaffected siblings,and normal control children. Our specific objectives wereas follows: (1) to address the hypothesis that preschizo-phrenia children have higher rates of behavioral and lan-guage deviance than normal control children; (2) to exam-ine whether childhood behavior and languageabnormalities are present in the unaffected siblings ofschizophrenia patients; (3) to determine the developmen-tal time course of the emergence of diese signs; and (4) toexamine subgroup issues, with the hypothesis thatpreschizophrenia subjects with an early age at first hospi-talization, with a history of fetal oxygen insufficiency, orwith both will be more severely affected in early child-hood. These questions were addressed within the contextof a cohort study of individuals enrolled in thePhiladelphia cohort of the National CollaborativePerinatal Project (NCPP).

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Childhood Behavioral Deviance and Language Abnormalities Schizophrenia Bulletin, Vol. 26, No. 2, 2000

Methods

Subjects and Psychiatric DiagnosesFormation of cohort. From 1959 to 1966, the NCPP

enrolled for study 9,236 offspring of 6,753 mothers whodelivered at two inner-city hospital obstetric wards inPhiladelphia—the Pennsylvania Hospital and theChildren's Hospital of Philadelphia (Niswader andGordon 1972). The offspring in over 90 percent of all thedeliveries at these two sites during the sampling periodwere enrolled. Fifty-four percent (n = 4,956) of the cohortmembers were the only children from their familiesenlisted in the study, and the remaining 46 percent {n -4,280) were from families with two or more children par-ticipating. The recruitment sites for the Philadelphiacohort were chosen to result in a predominantly African-American cohort (88%), thus permitting ethnic balanceacross the NCPP study sites overall.

Diagnostic screening and evaluation. In January1996, we conducted a search of the Perm LongitudinalDatabase (Rothbard et al. 1990), a citywide data base forregistration of contacts with public mental health facilitiesin Philadelphia from 1985 to 1995, ascertaining 1,197individuals whose names and dates of birth matched thoseof subjects in the birth cohort. In total, 339 (3.7%) of thecohort members had ever had a psychotic disorder diag-nosis (194 with schizophrenia or schizoaffective disorderand 145 with affective or drug-induced psychosis), and858 (9.3%) had ever had nonpsychotic disorder diagnoses(i.e., affective, anxiety, adjustment, developmental, andsubstance abuse disorders). Thus, this study relied onprevalent, rather than incident, cases.

Because these register diagnoses were assigned by hun-dreds of different clinicians in many different treatment set-tings without an explicit attempt to standardize diagnosticprocedures and criteria, they are unlikely to have a sufficientdegree of precision in differentiating schizophrenia fromother psychotic disorder categories. We therefore undertooka diagnostic validation study based on a review of the psy-chiatric medical records of the psychotic-disorderedprobands. We reviewed medical records for 144 suchprobands who had been treated at 15 mental health facilitiesthat agreed to cooperate with the study team in providingaccess to medical records. The remaining psychotic-disor-dered probands whose charts were not reviewed {n = 195)had been treated at facilities that no longer existed, refusedto cooperate, or were not contacted because only oneproband had been treated there. The participating facilitiesincluded inpatient services, day treatment clinics, and casemanagement services and were in all apparent ways equiva-lent to the nonparticipating facilities.

Six diagnosticians (two psychiatrists, two clinicalpsychologists, and two advanced graduate students in

clinical psychology) performed the chart reviews. An ini-tial set of ten charts was used in training to calibrate theless experienced with the more experienced diagnosti-cians. A standard coding form was used to record infor-mation pertinent to DSM-IV (American PsychiatricAssociation 1994) diagnostic criteria, differential diagno-sis of schizophrenia and affective disorders, age at onset(defined as the age of first psychotic symptoms, or, if notspecified, the age of first treatment contact), and course.In the vast majority of cases the information present in therecords spanned many years of the patient's illness, and aclear picture of the duration and primacy of psychoticsymptoms emerged. Of the 144 cases whose charts werereviewed, 72 received a DSM-TV diagnosis of schizophre-nia or schizoaffective disorder, 41 were diagnosed as hav-ing a psychotic form of major depressive disorder or bipo-lar disorder, and the remaining 31 were given a primarydiagnosis of substance abuse, anxiety disorder, atypicalpsychosis, psychotic disorder caused by a general medicalcondition, personality disorder, or adjustment disorder.For a randomly selected sample of 94 of the cases(excluding those used in training), charts were evaluatedindependently by two or more different examiners, withgood agreement on the diagnosis of schizophrenia andschizoaffective disorder (K = 0.85). There was only mod-erate agreement between the chart-based DSM-IV diag-noses of schizophrenia and schizoaffective disorder withthe original register diagnoses (K = 0.63) (see Cannon etal. 2000b, in this issue, for further detail on reliability pro-cedures).

The 72 cases with chart-review-based DSM-TV diag-noses of schizophrenia or schizoaffective disorder werefound not to differ significantly from the remaining 121probands with register diagnoses of schizophrenia orschizoaffective disorder (whose charts were not reviewed)in terms of gender, year of birth, birth order, mother's ageat birth, years of parental education, socioeconomic sta-tus, number of unaffected siblings enrolled in the NCPPstudy, or history of OCs (see Cannon et al. 2000b, in thisissue).

Demographics of comparison groups. The 72 caseswith chart-review-based DSM-IV diagnoses of schizo-phrenia or schizoaffective disorder had 63 unaffected sib-lings who were also NCPP study participants. Thirty-threechart-review schizophrenia subjects had no siblings, 23had 1 sibling, 11 had 2 siblings, 3 had 3 siblings, 1 had 4siblings, and 1 case had 5 siblings. (Note that we couldinclude only those siblings who were NCPP participantsbecause only NCPP participants had the relevant obstetricinformation available.) The 63 siblings included 7 with ahistory of psychiatric treatment (1 with psychosis not oth-erwise specified, 1 with mental retardation, and 5 withaffective and anxiety disorders) and 56 without such a his-

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Schizophrenia Bulletin, Vol. 26, No. 2, 2000 C.E. Bearden et al.

tory. For the normal comparison group we used the cohortmembers without a sibling diagnosed with schizophreniaand who according to our psychiatric screen had not beentreated in a public mental health facility in greaterPhiladelphia as an adult (n = 7,941). The remaining 1,160members of the original cohort were excluded from theanalyses. There were four categories of excluded subjects:(1) 72 cases with a history of treatment for a psychoticdisorder who were determined not to have schizophreniaOT schizoaffective disorder by chart review, (2) 194 caseswith a history of treatment for a psychotic disorder whosecharts were not reviewed (i.e., 195 minus 1 included sib-ling of an included schizophrenia subject), (3) 852 caseswith a history of treatment for a nonpsychotic psychiatricdisorder (i.e., 858 minus 6 included siblings of includedschizophrenia subjects), and (4) 42 cases of fetal orneonatal death.

Table 1 gives demographic characteristics on thethree groups of subjects of primary interest to the presentstudy: (1) cases with chart-review-based DSM-IV diag-noses of schizophrenia or schizoaffective disorder (n =72), (2) unaffected siblings of the confirmed schizophre-nia and schizoaffective probands (n = 63), and (3)nonpsychiatric controls (n = 7,941). The median age atfirst treatment contact—17 years in this sample—wasused to categorize the schizophrenia patients into thosewith early and later ages at first treatment. There was nota significant difference in age at first treatment betweenmale and female patients (two-tailed p = 0.6).

As seen in table 1, schizophrenia subjects were morelikely than their unaffected siblings or nonpsychiatric con-trols to be male, were more likely to be firstborn, andwere of lower socioeconomic status than nonpsychiatriccontrols. Moreover, schizophrenia subjects and their unaf-fected siblings were more likely to be African-Americanthan the nonpsychiatric controls.

MeasuresBehavioral Variables. We examined two categories

of behavioral problems: global social maladjustment andfocal deviant behaviors. The social maladjustment vari-able was derived from behavioral assessments conductedby a clinical psychologist at 8-12 months, 3-4 years, and7-8 years of age. The number of cohort subjects exam-ined at each assessment was as follows: 90 percent (n =8,356) at 8 months, 69 percent (n = 6,366) at 4 years, and81 percent (n = 7,450) at 7 years of age. At each timepoint, the clinician assessed the child on a multi-itembehavior rating inventory that rates various aspects of thechild's behavior in the testing situation on a scale rangingfrom 1 (hypo- or underresponding) to 5 (hyper- or over-responding), with a rating of 3 being "normal" (table 2).On the basis of this measure, a summary rating of "nor-mal," "suspect," or "abnormal" behavioral functioningwas then assigned by the clinician. Because of the non-continuous nature of this behavioral rating scale, datawere analyzed dichotomously; hence, social maladjust-ment at the 8-month, 4-year, and 7-year assessments wascoded as positive if the child received a rating of "abnor-mal" on the behavioral examination at that time point.Behavioral data were available for 51 schizophreniaprobands, 40 unaffected siblings, and 5,788 nonpsychi-atric controls at the 8-month assessment; 49 schizophre-nia probands, 37 unaffected siblings, and 5,541 nonpsy-chiatric controls at 4 years; and 48 schizophreniaprobands, 46 unaffected siblings, and 4,907 nonpsychi-atric controls at the 7-year assessment.

At ages 4 and 7, an additional rating of "deviantbehaviors" was assigned by the examining clinician.Specifically, this measure of focal signs of behavioraldeviance consisted of the following items: thumbsucking,nail biting, meaningless hand motions, meaninglesslaughter, excessive crying, echolalia or otherspeech dif-

Table 1. Soclodemographic characteristics by adult diagnostic group outcome

Characteristic

n

African-American, %

Female, %

Firstborn, %

SES, mean (SD)

Mother's age, mean yrs (SD)

Parental education1

Schizophreniaprobands

72

97

34.70

28.40

2.9(1.8)

24.2 (6.6)

10.4(2.4)

Unaffectedsiblings

63

100

49.21

9.50

2.6 (2.0)

22.9 (4.8)

10.1 (2.5)

Nonpsychiatriccontrols

7,941

87

49.70

24.40

3.4(1.9)

23.8(6.1)

10.6(2.5)

x'orF(df=2)

15.98

7.15

8.12

8.20

0.92

1.29

P

0.001

0.04

0.02

0.001

0.40

0.03

Note.—SES = socioeconomic status.1 Number of years of formal schooling.

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Table 2. Behavioral assessment Items

Infant behavior profile(8-mo evaluation) 4-yr behavior Inventory 7-yr behavior Inventory

Speed, duration, and intensity

of response to objects

Persistence of pursuit

of object

Intensity of social response

Nature of social response

to examiner

Nature of social response

to mother

Emotional reactivity

Degree of irritability

Degree of dependency

Duration of attention span

Degree of cooperation

Goal orientation

Response to directions

Level of activity

Nature of activity

Nature of communication

Fearfulness

Level of frustration tolerance

Emotional reactivity

Degree of dependency

Duration of attention span

Degree of cooperation

Goal orientation

Level of activity

Nature of activity

Nature of communication

Reaction to separation from mother

Fearfulness

Rapport with examiner

Self-confidence

Level of frustration tolerance

Assertiveness

Hostility

ficulties, stereotyped behavior, and/or other deviantbehaviors. Such behaviors are often reported to be pre-sent in children with early-onset schizophrenia or autisticspectrum disorders (Alaghband-Rad et al. 1995; Gupta etal. 1995). Subjects were rated on the number of thesedeviant behaviors that were coded as positive from thepsychological examination administered at each timepoint.

Speech and language variables. At age 7, 29 per-cent of the cohort (n = 2,085; 21 schizophrenia probands,17 unaffected siblings, and 2,047 nonpsychiatric controls)were administered a speech, language, and hearing exami-nation by a speech pathologist This test assessed recep-tive and expressive language ability, as well as speechmechanism and production. From the child's performanceon this test, a summary rating of speech intelligibility wasobtained. Speech was coded as abnormal if the childreceived a rating of 3 or greater ("considerable difficultyunderstanding what child says," "child has verbalized butis unintelligible," or "no speech") on this speech intelligi-bility summary variable.

Subjects were also evaluated with a quantitativemeasure of language ability at age 7, the Auditory-VocalAssociation Test (Kirk et al. 1961). This test wasadministered to 76 percent of the subjects (59 schizo-phrenia probands, 48 nonschizophrenia siblings, and6,008 nonpsychiatric controls) and assesses expressivelanguage ability and word associations. Age-correctedstandard scores were collapsed into five performance

levels (percentile ranges of the norming populationsappear in parentheses): (1) high average to superior(75th to 99th percentile), (2) average (25th to 74th per-centile), (3) low average (9th to 24th percentile), (4)borderline (3rd to 8th percentile), and (5) deficient (1stto 2nd percentile).

Obstetric variables. We modeled three classes of obstet-ric influences that could be related to premorbid cognitivedeficits in schizophrenia: hypoxia-associated OCs, other(prenatal) OCs, and birth weight. A detailed description ofthe formation of the hypoxia-associated OCs scale andprenatal OCs scale is provided elsewhere (see Cannon etal. 2000b, in this issue). Briefly, the hypoxia-associatedOC scale was formed by selecting complications consid-ered to be either direct (blue at birth, required resuscita-tion, neonatal cyanosis, neonatal apnea) or indirect(abnormalities of fetal heart rate or rhythm, umbilicalcord knotted or wrapped tightly around neck, thirdtrimester bleeding, placental hemorrhaging or infarcts,polyhydramnios, meconium in amniotic fluid, breech pre-sentation) indicators of fetal oxygen insufficiency. Theindirect indicators were chosen based on empirical valida-tion against direct hypoxia indicators in prior studies(Low et al. 1992, 1995; Arabin et al. 1993; Maier et al.1994; Adamson et al. 1995; Salafia et al. 1995). Each ofthe indirect indicators was also significantly predictive ofone or more of the direct hypoxia indicators in this cohortWe did not weight the indirect indicators according to the

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strength of this association, however, because the directindicators reflected hypoxia at or shortly after birth,whereas many of the indirect indicators could reflecthypoxia prior to birth (sensitivity to which would bereduced if the items were weighted according to theirrelationship with birth hypoxia). Each complication con-tributed 1 point to the total hypoxia-associated OC score.

Five prenatal OCs that were not significantly associ-ated with the direct hypoxia measures in this sample (andwhose primary impact on the fetus was unlikely to beoxygen deprivation) were included in a prenatal OCsscale: maternal infection during pregnancy (includingviral, bacterial, and fungal), maternal cardiovascular ill-ness during pregnancy, maternal pulmonary illness duringpregnancy, maternal hematologic illness during preg-nancy, and maternal endocrine illness during pregnancy.Again, each complication contributed 1 point to the scaletotal.

Statistical analyses. Because it was possible for there tobe more than one subject from the same family of originwithin an outcome group, and because individuals fromthe same family are likely to be more alike than unrelatedindividuals, it was first necessary to reduce the degrees offreedom available for analysis in order to preserve theassumption of independence of observations. This wasachieved by computing averages of the test scores andcovariates within each family, separately by diagnosticgroup. To determine whether the familywise analysesobscured any relationships among variables that were pre-sent at the level of individuals, the analyses were also per-formed using the individualized data. There were no dif-ferences in the relationships that were and were notsignificant between the two analytic approaches.Therefore, we report the results using only the data inwhich each observation in each diagnostic group is uniquewith respect to family of origin. Averaging the test scores(and covariates) within each family separately for eachdiagnostic group produced a total of 51 unique observa-tions in the proband group, 29 unique observations in thesibling group, and 4,648 unique observations in the con-trol group for the analyses of social maladjustment at 8months. For social maladjustment at ages 4 and 7, thenumbers of unique observations were 49 and 48 in theproband group, 26 and 30 in the sibling group, and 4,484and 4,056 in the control group. For deviant behaviors atages 4 and 7, the numbers of unique observations were 49and 65 in the proband group, 26 and 32 in the siblinggroup, and 4,492 and 4,922 in the control group. Forabnormal speech at age 7, the corresponding numberswere 21, 12, and 1,842, respectively, and for the Auditory-Vocal Association Test at age 7, the numbers were 59, 31,and 4,664, respectively.

Each measure of behavioral function or speech andlanguage function was then tested for association withdiagnostic outcome in a separate logistic regression analy-sis by method of generalized logits (Stokes et al. 1995).The outcome measure classified the cohort members intothree groups: probands, siblings, and controls. Gender andrace were included as categorical predictors, and age atexamination, parental education (mean number of years ofschooling), and socioeconomic status (reflecting the occu-pation and income of primary wage earner on a scale of 1(unemployed, on public assistance) to 9 (professional,upper middle class)) were included as interval-scale pre-dictors. An adjusted odds ratio (OR) and its 95 percentconfidence interval (CI) was computed for each predictorcontrasting schizophrenia subjects and the unaffected sib-lings of schizophrenia subjects with cohort members withno psychiatric diagnoses. We also evaluated whether dif-ferences in childhood behavioral and language functioningamong the diagnostic groups were moderated by gender orparental socioeconomic status, and whether childhood dys-function in the schizophrenia group was specific to thosewith an early age at first treatment contact

Results

Childhood Behavioral Impairment and AdultDiagnostic Outcome. Table 3 presents the ORs, 95 per-cent CIs, and p values for the retained predictors on riskfor each outcome considered separately. There were nodifferences in social maladjustment between preschizo-phrenia subjects and controls at age 8 months (x2 = 1.35,df=l,p = 0.25) or at age 4 (x2 = 1.62, df=\,p = 0.20).However, by 7 years of age, significant differencesbetween schizophrenia subjects and controls had emergedin the behavioral domain. After controlling for age, sex,race, parental education level, and parental socioeconomicstatus, we found social maladjustment at age 7 to be themost potent predictor of schizophrenia outcome (x2 =7.90, df = 1, p = 0.005, OR = 2.54, 95% CI = 1.33-4.86).hi contrast, unaffected siblings of schizophrenia subjectsdid not show impairment on this measure of behavioralfunctioning at age 8 months (x2 = 2.08, df= 1, p = 0.15),4 years (x2 = 0.49, df=l,p = 0.48), or 7 years (x2 = 0.71,df= I, p = 0.40).

Both preschizophrenia subjects and their unaffectedsiblings showed significantly higher rates of focal deviantbehaviors relative to controls. Deviant behavior was a sig-nificant predictor of adult schizophrenia at both age 4 (x2

= 6.93, df = 1, p = 0.009, OR = 1.68, 95% CI =1.14-2.46) and age 7 (x2 = 6.79, df= 1, p = 0.009, OR =1.65, 95% CI = 1.13-2.41) after controlling for age, sex,race, parental education level, and parental socioeconomic

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status. Further, as seen in figure 1, the rate of schizophre-nia steeply increased with the number of deviant behav-iors shown at both age 4 and age 7, such that the preva-lence of schizophrenia outcome among those with three ormore of these deviant behaviors was over 5 times that ofthose with no signs of deviant behaviors in the age 4analysis, and approximately 4 times that of those with nosigns of deviant behavior at age 7. Deviant behavior wasalso a significant predictor of sibling status at both age 4(X2 = 4.57, df= 1, p = 0.03, OR = 1.80, 95% CI =1.05-3.10) and age 7 (x2 = 5.67, df=l,p = 0.02, OR =1.85, 95% CI = 1.12-3.10). In the age 4 analysis, althoughunaffected siblings of schizophrenia patients were over-represented among those showing one sign of deviantbehavior, the prevalence rate did not increase in a linearfashion (figure 2). However, at age 7 the rate of siblingstatus did show a linear increase with increasing numberof deviant behaviors (figure 2).

Childhood Speech and Language Abnormality andAdult Diagnostic Outcome. Table 4 presents the ORs, 95percent CIs, and p values for the language measures foreach outcome considered separately. After controlling forage, sex, race, parental education level, and parental socioe-conomic status, abnormal speech at age 7 was found to be ahighly significant predictor of schizophrenia outcome (x2 =9.19, # = \,p = 0.002, OR = 12.70,95% Cl = 2.46-65.66).

While the speech of unaffected siblings did not fallinto the clinically abnormal range, both schizophreniasubjects and their unaffected siblings performed morepoorly than controls on the Auditory-Vocal AssociationTest at age 7. After controlling for age, sex, race, parentaleducation level, and parental socioeconomic status, levelof performance on this test was found to be the most sig-nificant predictor of outcome, achieving a significant neg-ative association with schizophrenia (x2 = 9.07, df = 1, p= 0.002, OR = 0.71, 95% CI = 0.57-0.89) and with sib-ling status (x2 = 14.02, df= 1, p = 0.0002, OR = 0.55,95% CI = 0.40-0.75). Further, as shown in figure 3,preschizophrenia subjects and their unaffected siblings areunderrepresented at the highest levels of language abilityand are progressively more overrepresented acrossdecreasing ability levels on this test

Obstetric Variables. In the analyses of the obstetric vari-ables in relation to behavioral measures at each timepoint, a history of fetal hypoxia did not differentiallycharacterize preschizophrenia subjects with premorbidsocial maladjustment at age 7 (x2 = 1.9, df= 1, p = 0.38)or deviant behaviors (age 4: x2 = 0.12, df= 1, p = 0.72;age 7: x2 = 0.04, df - 1, p = 0.84), nor were preschizo-phrenia subjects with low birth weight or a history of pre-natal OCs more likely to show either social maladjust-ment or deviant behavior at any time point.

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Figure 1. Crude prevalence rates of adult schizophrenia by number of deviant behaviors at age 4and age 71

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Figure 2. Crude prevalence rates of unaffected sibling (of a schizophrenia patient) status by numberof deviant behaviors at age 4 and age 7

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Although fetal hypoxia did not differentially charac-terize preschizophrenia subjects with premorbid behav-ioral signs, there was a trend relationship between fetalhypoxia and the presence of deviant behaviors in theoverall cohort at age 7 (x2 = 3.63, ctf = 1, p = 0.057, OR =1.1, 95% Q = 0.91-1.3) but not at age 4 (x2 = 1.68, df =l,p = 0.20, OR = 0.93, 95% Cl = 0.82-1.04). History ofhypoxia was not related to social maladjustment in theoverall cohort at either time point (age 4: x2 = 0.945, df=l ,p = 0.82; age 7: x2 = 1.56, df=\,p = 0.21).

Further, there was no significant interaction betweenperformance level on the Auditory-Vocal Association Testand a history of fetal hypoxia (x2 = 0.16, df= 2, p = 0.69),low birth weight (x2 = 0.71, df = 2, p = 0.40), or prenatalOCs (x2 = 0.12, df=2,p = 0.73).

Potential Moderating Variables. In the analyses of gen-der and parental socioeconomic status as potential moder-ators of the effects of diagnosis in relation to childhoodsocial maladjustment at age 7, there were no significantinteractions of diagnosis with gender (x2 = 1-59, df=2,p= 0.45) or parental socioeconomic status (x2 = 1.4, df= 2,p = 0.50). Similarly, there were no significant interactionsbetween deviant behavior and gender (age 4: x2 = 0.67, df= 2,p = 0.72; age 7: x2 = 0.05, df=2,p = 0.98) or parentalsocioeconomic status (age 4: x2 = 0.51, df= 2, p = 0.78;age 7: x2 = 4.98, df=2,p = 0.08), or between level of per-formance on the Auditory-Vocal Association Test andeither gender (x2 = 1.05, df = 2, p = 0.59) or parentalsocioeconomic status (x2 = 1.07, df= 2,p = 0.59).

Further, in this study premorbid behavioral and lan-guage disturbance were not confined to an early-onsetsubgroup of schizophrenia subjects: preschizophreniasubjects with an early age at first treatment contact wereno more likely to show social maladjustment (x2 = 1.9, df= 1, p = 0.67), deviant behavior (age 4: x2 = 3.5, df= 1, p= 0.06; age 7: x2 = 0.22, df = 1, p = 0.64), or abnormalspeech (x2 = 2.01, df= \,p = 0.16) than those first treatedat a later age. Poor performance on the Auditory-VocalAssociation Test also was not confined to an early-onsetsubgroup of schizophrenia patients (x2 = 2.88, df= \,p =0.09).

Discussion

The results of this study contribute to an increasing bodyof evidence that behavioral and language deviance inearly childhood is predictive of adult schizophrenia. Wefound that preschizophrenia subjects displayed increasedrates of deviant behaviors as early as age 4, while signs ofsocial and language impairment became evident by age 7,suggesting that the profound impairments of language andsocial behavior that characterize adult schizophrenia are

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Figure 3. Crude prevalence rates of adult schizophrenia (diamonds) and of being an unaffectedsibling of a schizophrenia patient (squares) by Auditory-Vocal Association Test score categoryat age 71

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present at least to some degree from very early in life.This pattern suggests that the diathesis for schizophreniais manifested across multiple domains of function and thatdeviance may become evident across an increasing num-ber of functional domains over the course of develop-ment. Further, our findings of qualitatively similar signsof deviance in siblings who do not become schizophrenicin adulthood are consistent with numerous prior studies ofchildren at elevated genetic risk for schizophrenia(reviewed in Mednick and Silverton 1988 and Olin et al.1996). Given that a substantial number of the first degreerelatives of schizophrenia patients carry a predisposinggenotype without manifesting the disorder phenotypically(Gottesman and Bertelsen 1989), this pattern is consistentwith an association between presence of a genetic diathe-sis to schizophrenia and expression of functional devianceduring childhood, although it remains possible that sharedenvironmental factors not accounted for by parental edu-cation level and parental socioeconomic status may alsobe relevant

Behavioral Abnormalities. While only preschizophreniaindividuals displayed early signs of social maladjust-ment, both schizophrenia patients and their unaffectedsiblings displayed focal signs of deviant behavior at bothage 4 and age 7. Such behaviors have been reported inprevious studies to be common prodromal signs of schiz-ophrenia, particularly among those with a severe early-onset illness (Alaghband-Rad et al. 1995; Gupta et al.1995). This pattern of findings suggests that deviant

behaviors may indicate underlying genetic susceptibilityto the disorder, whereas social maladjustment may markthe onset of the clinical phenotype; that is, the emergenceof marked maladaptive social behavior may mark thebeginning of a pathway to progressively greater behav-ioral deviance, culminating eventually in psychoticsymptoms. Because the assessments were discontinued atage 7, their subsequent developmental trajectory remainsto be characterized.

However, an unknown degree of measurement errorexists in these behavioral measures because of thearchival nature of the data. Thus, such factors as potentialinterviewer bias resulting from parental attributes cannotbe ruled out, and the degree of reliability across examin-ers cannot be determined. While such methodologicallimitations must be considered, this study—the first toobtain prospective, standard data gathered by profession-als—nevertheless significantly improves upon previouswork.

Abnormalities of Language. Evidence of aberrant lan-guage development at age 7 suggests that the profoundlanguage disturbance seen in adult schizophrenia mayhave its roots in early childhood development Althoughthe sample size available for analysis was limited, giventhat abnormal speech at age 7 was associated with agreater than twelvefold increase in risk for adult schizo-phrenia, it appears that premorbid language dysfunctionmay be one of the most potent predictors of future schizo-phrenia illness. Further, while unaffected siblings did not

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fall into the clinically abnormal range, they also showedimpaired language development relative to normal con-trols on a quantitative measure of language function, theAuditory-Vocal Association Test. This finding suggeststhat signs of early language deviance may manifest in amore subtle form in those who are at heightened geneticrisk but do not develop the illness.

Developmental Time Course of PremorbidDysfunction. It appears that the phenotypic manifesta-tions of the vulnerability to schizophrenia may beexpressed in an age-dependent manner, as there were nofunctional differences between preschizophrenia subjectsand nonpsychiatric controls at the 8-month assessment,focal deviant behaviors became manifest by age 4, andlanguage deviance and social maladjustment did notbecome evident until age 7. Such findings are consistentwith other investigators' findings of increased behavioraldeviance with increasing age (Watt 1978; Neumann et al.1995). One interpretation of this pattern is that, as therequirements of normality become relatively greater withage, preschizophrenia subjects become progressivelymore deviant from their peers. Another not mutuallyexclusive possibility is that early events may initiate acascade of progressively more impaired function, result-ing ultimately in the development of psychotic illness.However, it is possible that subtle differences between thetwo groups were present at 8 months but that the mea-sures used were not sufficiently sensitive to detect thosedifferences. The Bayley Scales, used in the 8-monthassessment, have been reported to be unreliable by somerecent investigations because of lack of standardizedadministration (e.g., Gauthier et al. 1999), and measuresof behavioral function among very young children may beless reliable than those used with older children (e.g.,Eyberg 1985; Harris and Liebert 1987). Arguing againstthis interpretation, however, is the fact that schizophreniasubjects and controls did not differ on any measure offunctioning (i.e., Infant Behavior Exam, Bayley Test ofMotor Development, and neurological exam) at the 8-month assessment (also see Rosso et al., this issue).Possibly, abnormalities must be particularly striking to benoted by a clinician at this time point.

Subgroup Issues. Counter to some previous, smaller scalestudies (Fish 1987; Lewis and Murray 1987; O'Callaghanet al. 1991), we failed to find any relationship between pre-morbid functional indicators and three types of OCs: fetalhypoxia, low birth weight, and pregnancy complications.However, it is possible that the effects of hypoxia-relatedOCs or other obstetric variables on behavioral and lan-guage function may not be detectable as early as age 7, andthe manifestation of the effects of OCs may depend on the

maturational stage of the brain regions that underlie thesefunctions (Lipska et al. 1993). Thus, our results do not ruleout a contribution of OCs to premorbid behavioral and lan-guage abnormalities in schizophrenia but do constrain theperiod during which such a relationship could be apparent.Nevertheless, our findings indicate that premorbid behav-ioral and language impairment is not limited to a subgroupof severely affected, early-onset individuals, nor does it dif-ferentially characterize those who suffered from fetalhypoxia, pregnancy complications, or low birth weight.Thus, if there is heterogeneity in etiologic factors, thosewho suffered from these OCs do not appear to form a quali-tatively distinct subgroup of severely affected individuals,at least with respect to childhood behavioral and languageimpairments. While our analyses of dichotomous measuresof behavioral and language functioning confirmed premor-bid deviance in a subgroup of preschizophrenia subjects,the analysis of quantitative measures revealed increasedprevalence of schizophrenia outcome with increasing num-bers of deviant behaviors and across decreasing levels oflanguage ability on the Auditory-Vocal Association Test.Further, our analyses of continuous, normally distributedmeasures of IQ provide no evidence that risk of schizophre-nia is confined to a subgroup of the population (see Cannonet al. 2000a, in this issue). Thus, the use of the dichotomousfunctional measures "deviant" and "not deviant" mayobscure more subtle early differences that actually existamong schizophrenia patients, their relatives, and controlsubjects, as only those individuals displaying obvious signsof impairment are categorized as deviant. It may be, then,that the "neurodevelopmental subtype" described in previ-ous studies (Murray and Lewis 1988; Crow 1989;Neumann et al. 1995) represents not a qualitatively distinctcategory of preschizophrenia individuals but the tail end ofa continuum of risk.

Ethnic Composition of Birth Cohort. This is the firstreported study of antecedents of schizophrenia in a pre-dominantly African-American birth cohort. Our findingsare consistent in many ways with other prospective birthcohort studies of predominantly Caucasian subjects (Joneset al. 1995; Cannon et al. 1997; Jones and Done 1997). Itis notable that the number of cohort members with regis-ter diagnoses of schizophrenia results in a prevalence esti-mate that is quite high (i.e., 2.1%, even before taking intoaccount the possibility of unascertained cases), whichraises the question of whether the cohort is unusual withrespect to the distribution of risk factors for schizophre-nia. It remains controversial whether rates of schizophre-nia vary by factors such as urban residence, social class,and minority status; the variability of these factors isgreatly restricted in this cohort compared with the generalpopulation. However, given that the rate of OCs is also

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higher in this cohort (Cannon et al. 2000a, in this issue), itmay be that the higher than usual rate of schizophreniareflects the higher than usual base rate of OCs, which inturn may reflect its sociodemographic profile (see Cannonet al. 2000a, in this issue, for further discussion of thisissue). Unfortunately, the truncated racial diversity of thissample precluded the examination of race as a modifier ofthe behavioral and language variables. Thus, althoughthere is no evidence for a race-specific effect, the possiblerole of ethnic differences in the development of psychi-atric disorders merits further study.

Limitations. Although we have attempted to addresspotential limitations of this study in our design of the proj-ect, some of these limitations could not be completelyeliminated. First, our ability to ascertain cohort membersas adults was dependent on whether they were still resi-dents of the Philadelphia area and were eligible for and/orutilized public health facilities. Because we have no sys-tematic method to determine the percentage of cohortmembers who moved away from Philadelphia or utilizedprivate health facilities exclusively, it is unclear whetherthere was selective attrition.

Incomplete ascertainment of schizophrenia probandsfrom the control sample could also produce a biasing effectSpecifically, a false-positive association could result if asubstantial number of unidentified cases of schizophreniawere included in the sample classified as nonpsychiatriccontrols and such cases had substantially better childhoodbehavioral and language functioning than the cases whowere ascertained. It is indeed virtually certain that somecases of schizophrenia were classified as nonpsychiatriccontrols in the analyses (i.e., female patients whose lastnames changed at marriage, patients who sought treatmentprior to 1985 or after 1995, patients who moved out ofPhiladelphia prior to 1985, patients who did not seek treat-ment, or patients whose treatment was exclusively via pri-vate practitioners). The extent of this misclassification can-not be quantified precisely. Nevertheless, while we cannotcompletely rule out the possibility of such an ascertainmentbias, there is no reason to suspect that the premorbid behav-ioral and language functioning of the unascertained schizo-phrenia subjects in the control group is different from thatof the ascertained cases. It could be argued that the mem-bers of the cohort with poorer functioning were more likelyto stay in the vicinity where they were bom, in which caseour ascertainment methods would have oversampled theschizophrenia cases from the lower levels of behavior andlanguage functioning. To address this possibility, we com-pared the schizophrenia cases with the sample of individu-als who were identified as having nonpsychotic forms ofmental illness in the Philadelphia area treatment data base.Any tendency for the more disabled subjects to remain in

the locations of their births (and/or for more behaviorallyintact subjects to have moved out of the area) should haveaffected our ascertainment of these nonpsychotic cases aswell. If a bias toward ascertainment of behavior- and lan-guage-disabled subjects exists, the schizophrenia casesshould not differ from the nonpsychotic cases ascertainedin the register. However, the schizophrenia subjects did infact have more deviant behaviors (age 4:x2 = 3.16, df= I,p = 0.07; age 7: %2 = 4.08, df= 1, p = 0.04) and social mal-adjustment (x2 = 5.38, df = 1, p = 0.02) and abnormal lan-guage at age 7 (x2 = 6.52, df= \,p = 0.01) than the nonpsy-chotic register cases. That the deviant behavior analysis atage 4 fell short of statistical significance likely reflects thepresence of unaffected siblings in the control group. In fact,when the primary analyses were repeated including thenonpsychotic register cases with the nonpsychiatric cohortmembers as controls, the controls continued to have signifi-cantly better social functioning and language functioning at7 years than the schizophrenia patients (social: x2 = 10.20,df= 1, p = 0.001, OR = 2.89, 95% CI = 1.5-5.5; language:X2 = 9.64, df = 1, p = 0.001, OR = 12.8, 95% CI =2.6-63.9) and to have significantly fewer deviant behaviorsthan both the schizophrenia patients at both ages (age 4: x2

= 6.94, df= 1, p = 0.008, OR = 1.67, 95% a = 1.1-2.5;age 7: x2 = 5.94, df= 1, p = 0.01, OR = 1.58, 95% CI =1.1-2.3) and their siblings at age 7 (x2 = 5.34, df = l,p =0.02, OR = 1.6, 95% CI = 1.1-2.4). The comparisonbetween controls and unaffected siblings reached trend sig-nificance at age 4 (x2 = 2.99, df=l,p = 0.08, OR = 1.53,95% CI = 0.96-2.5). Further, both preschizophrenia sub-jects and their unaffected siblings continued to score morepoorly than controls on the Auditory-Vocal Association Testat age 7 (schizophrenia subjects: x2 - 7.99, df = 1, p =0.005, OR = 0.73, 95% CI = 0.58-0.91; siblings: x2 =13.20, df=l,p = 0.0003, OR = 0.56,95% CI = 0.41-0.77).

A further threat to validity of these study findingscould result from misdiagnosis of chart review cases.Independent evaluations of a random sample of medicalrecords by different reviewers produced a high rate ofdiagnostic agreement (K = 0.85, 93% simple agreement),indicating that our chart-review diagnoses are reliable.However, this does not guarantee validity of these diag-noses. It is important to note that invalid assignment ofschizophrenia or schizoaffective diagnoses by chartreview would produce a false-positive result only if thepremorbid behavioral and language deficits were confinedto the cases whose actual diagnoses were not schizophre-nia or schizoaffective disorder. The diagnoses most likelyto compete with those assigned are psychotic forms ofbipolar or unipolar affective illness. To address this issue,secondary analyses were conducted of the 41 psychotic-disordered cases who were screened out of the probandsample because they received DSM-F/ diagnoses of bipo-

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lar or unipolar affective disorder by chart review; thesecases did not differ from controls on any measure ofchildhood behavioral function (social maladjustment, age7: x2 = 0.62, df= l,p = 0.73; deviant behavior, age 7: x2

= 3.40, df=l,p- 0.19) or language function (x2 = 0.15,df = 1, p - 0.93) or on most cognitive measures (seeCannon et al. 2000a, in this issue). Given this pattern, ifthere are misdiagnosed cases of affective psychosis in theDSM-N schizophrenia/schizoaffective group, the effecton the results should be an under- rather than overestima-tion of die associations between childhood behavioral andlanguage dysfunction and schizophrenia.

Finally, although our control sample consisted of indi-viduals who had not been treated in a public health facilityin Philadelphia for a psychiatric disorder, it is possible thatsuch individuals have a psychiatric disorder but neverreceived treatment or were treated elsewhere. Although ide-ally we would wish to exclude such individuals from thecontrol group, presumably their exclusion would onlyaccentuate the differences between the two groups.Similarly, while we ascertained that unaffected siblings ofindividuals with psychiatric diagnoses of schizophrenia oraffective disorder had not received treatment at a mentalhealth facility in the greater Philadelphia area, siblings mayhave been treated elsewhere or have untreated mental ill-ness. Ideally, outcome measures would be based on directclinical interview with patients and siblings; currently, afollowup study is under way to obtain lifetime psychiatrichistories of schizophrenia and affectively ill probands andtheir siblings. This followup study also involves neuropsy-chological and neuroimaging assessments of patients andsiblings, and thus will directly examine the covariation ofbehavioral dysfunction with underlying structural andphysiological dysfunction, while accounting for sources ofdeficits in terms of genetic and obstetric factors.

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Acknowledgments

This research was supported by grants from the March ofDimes Birth Defects Foundation, White Plains, NY, andthe Stanley Foundation, Bethesda, MD.

The Authors

Carrie E. Bearden, Ph.D., is Postdoctoral Fellow in ChildPsychology, and Laura E. Sanchez, M.D., is AssistantProfessor, Department of Psychiatry, University ofPennsylvania, Philadelphia, PA. Trevor Hadley, Ph.D., isProfessor of Psychology in Psychiatry, Department of

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Psychiatry, and Chief of the Center of Mental HealthPolicy Research, University of Pennsylvania. Isabelle M.Rosso, M.A., is Ph.D. Candidate in Psychology,Department of Psychology, University of Pennsylvania. J.Megginson Hollister, Ph.D., is Research AssistantProfessor, Department of Psychiatry, University ofUtrecht, Utrecht, The Netherlands. Tyrone D. Cannon,Ph.D., is Staglin Family Professor of Psychology,Psychiatry, and Human Genetics, Department ofPsychology, University of California, Los Angeles, CA.

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A Prospective Cohort Study of Childhood Behavioral Deviance and Language Abnormalities as Predictors...

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