thought disorder in mid-childhood as a predictor of adulthood diagnostic outcome: findings from the...

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Thought disorder in midchildhood as a predictor of adulthood diagnostic outcome: findings from the New York HighRisk Project

D. C. Gooding, S. L. Ott, S. A. Roberts and L. ErlenmeyerKimling

Psychological Medicine / FirstView Article / August 2012, pp 1 10DOI: 10.1017/S0033291712001791, Published online:

Link to this article: http://journals.cambridge.org/abstract_S0033291712001791

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Thought disorder in mid-childhood as a predictor ofadulthood diagnostic outcome: findings from theNew York High-Risk Project

D. C. Gooding*, S. L. Ott, S. A. Roberts and L. Erlenmeyer-Kimling

University of Wisconsin-Madison, Madison, WI, USA

Background. Thought disorder has been proposed as an indicator of schizotypy, which is considered to be necessary

but not sufficient for the development of schizophrenia. It is unclear whether thought disorder is an indicator of

susceptibility (i.e. an endophenotype) for schizophrenia. The goal of the present study was to elucidate the role of

thought disorder in relation to schizotypy by examining its presence in high-risk individuals during mid-childhood.

Method. The sample consisted of 265 subjects drawn from the New York High-Risk Project. Individuals at high risk

for schizophrenia (i.e. offspring of parents with schizophrenia) were compared with individuals at low risk for

schizophrenia (i.e. offspring of parents with affective disorder or offspring of psychiatrically normal parents).

Videotaped interviews were rated for thought disorder using the Scale for the Assessment of Thought, Language,

and Communication (TLC). The same subjects were administered diagnostic interviews in late adolescence/early

adulthood.

Results. Although positive thought disorder was equally present in subjects with affective and non-affective

psychoses, negative thought disorder (namely, poverty of speech and poverty of content of speech) was elevated only

in subjects with schizophrenia-related psychosis. Logistic regression analyses revealed that negative thought disorder

added to the prediction of schizophrenia-related psychosis outcomes over and above positive thought disorder.

Conclusions. These findings suggest that negative thought disorder may have a specific association with schizotypy,

rather than a more general association with psychosis. The findings also support consideration of negative thought

disorder as an endophenotypic indicator of a schizophrenia diathesis.

Received 21 December 2011 ; Revised 24 June 2012 ; Accepted 9 July 2012

Key words : Endophenotype, psychosis, schizophrenia, thought disorder.

Introduction

Early detection of endophenotypes is valuable because

of its potential to parse statistical high risk as well as

provide insight into the underlying pathophysiology

of a disorder. An endophenotype must be heritable,

relatively specific to the disorder in question, and in-

dependent of clinical status (Gottesman & Gould,

2003). The endophenotype would be maximally useful

if capable of predicting who among those at risk to

schizophrenia are most likely to develop the disorder.

However, not all variables differing between high-risk

individuals and controls function as predictors of later

clinical outcome (Erlenmeyer-Kimling et al. 2000). To

be a useful predictor, the expression of an endo-

phenotype must be identifiable sufficiently early to

enable intervention strategies to be introduced during

the brain’s maximum period of plasticity, prior to

clinical symptoms or prodromal signs appearing.

The New York High-Risk Project (NYHRP) has

emphasized the need to simultaneously consider nu-

merous plausible, easily accessible, and comparatively

low-cost measurable candidates for endophenotypes

(Erlenmeyer-Kimling, 1987; Erlenmeyer-Kimling et al.

2000). For instance, in the NYHRP, not only were

childhood deficits in sustained attention, short-term

memory and gross motor skills greater in offspring of

schizophrenic parents than in the two offspring com-

parison groups, but also these deficits cumulatively act

as a predictor of adulthood schizophrenia (Erlenmeyer-

Kimling et al. 2000). The databank contains additional

candidate endophenotypes, such as thought disorder

(TD), which we reported on previously (Ott et al.

2002; Gooding et al. 2012), and which we continue to

explore, mainly because of its importance to the

understanding of cognitive processes in schizophrenia.

* Address for correspondence : D. C. Gooding, Ph.D., University of

Wisconsin-Madison, Madison, WI, USA.

(Email : [email protected])

Psychological Medicine, Page 1 of 10. f Cambridge University Press 2012doi:10.1017/S0033291712001791

ORIGINAL ARTICLE

Thought disorder

Formal TD1# has been considered one of the cardinal

features of schizophrenia since Emil Kraepelin’s and

Eugen Bleuler’s time (Kraepelin, 1896/1919; Bleuler,

1911/1950). Paul Meehl (1962, 1989) proposed TD as

an indicator of schizotypy, the latent personality or-

ganization necessary but not sufficient for the devel-

opment of schizophrenia.

We consider TD a viable endophenotype of schizo-

phrenia liability. TD is found in non-affected family

members at a higher rate than in the general popu-

lation (Harvey et al. 1982 ; Shenton et al. 1989 ; Hain

et al. 1995 ; Docherty & Gordinier, 1999) and has a

heritable component (Berenbaum et al. 1985 ; Kendler

et al. 1995 ; Gambini et al. 1997 ; Docherty & Gottesman,

2000 ; Bashak et al. 2008). Prior research (Spohn et al.

1986 ; Marengo & Harrow, 1987; Levy et al. 2010)

shows that TD is state independent, i.e. it manifests in

an individual whether or not illness is active. Further,

within families, TD and schizophrenia-spectrum dis-

orders appear to co-segregate.

Although factor analytic studies support the multi-

dimensional nature of TD (Cuesta & Peralta, 2011),

there is no clear consensus regarding the exact type

and number of interpretable factors that comprise TD.2

Nonetheless, much research shows that while the

quantity of TD does not distinguish among the psy-

choses, the quality of TD differs (Marengo & Harrow,

1985, 1987 ; Andreasen, 1986 ; Holzman et al. 1986 ;

Shenton et al. 1987 ; Solovay et al. 1987). Despite the

non-specificity of TD per se, certain aspects of TD tend

to be more distinctive of one psychotic disorder than

others (Levy et al. 2010). Generally, schizophrenic TD

is characterized by combinatory thinking, confusion

and idiosyncratic verbalizations (Holzman et al. 1986),

or a prominent negative formal TD described as pov-

erty of speech and poverty of content (Andreasen &

Grove, 1986). In contrast, manic TD is characterized by

inappropriate flippancy and elaborate, playful con-

fabulations (Holzman et al. 1986), or a prominent

positive formal TD described as pressure of speech,

distractibility and loss of goal (Andreasen & Grove,

1986). One unresolved research question is whether

these differences can be used in the early detection and

prediction of later development of specific forms of

psychosis.

Prior TD findings from the NYHRP

Earlier analyses in the NYHRP demonstrated that TD

could be observed at mid-childhood in children at

genetic risk for psychosis, years before the onset of any

illness (Ott et al. 2002). These preliminary data, based

on a subset of the first sample of NYHRP’s two sam-

ples of high-risk and comparison children, are con-

sistent with data from independent family studies

(Shenton et al. 1989 ; Hain et al. 1995 ; Docherty &

Gordinier, 1999) in showing that relatives of schizo-

phrenia patients display TD. The findings of Ott

et al. (2002) based on ratings of Andreasen’s Scale

for the Assessment of Thought, Language, and

Communication (TLC; Andreasen, 1979) demon-

strated that negative TD was associated with an out-

come of schizophrenia-related psychosis (SRP),

independent of parental risk. The analyses also re-

vealed that TD was elevated in participants who de-

veloped schizo-affective disorder or affective disorder

in adulthood. Nevertheless, questions regarding the

relationship between positive and negative TD with

affective disorder versus SRP, and psychotic versus

non-psychotic disorders, were not examined, because

the earlier (Ott et al. 2002) analyses did not include an

affective psychosis comparison group.

More recent analyses (Gooding et al. 2012), based on

responses to Rorschach stimuli scored with Johnston

and Holzman’s Thought Disorder Index (Johnston &

Holzman, 1979), indicated that offspring of schizo-

phrenia parents displayed more TD than offspring of

either affective or normal parents. We also showed

that the presence of TD during late adolescence

(mean=19.6 years) is associated with a heightened

likelihood of the emergence of psychosis in adulthood.

These analyses provide further support for consider-

ing TD as an indicator of a psychosis diathesis. We

could not rule out the possibility that the offspring

later diagnosed as psychotic were in the prodromal

stages of the illness at the time of their Rorschach as-

sessment. Clearly, ratings of TD obtained in mid-

childhood are especially informative in this regard.

The earlier in the developmental trajectory that one

can identify deficits and aberrations with predictive

utility, presumably the greater the window of oppor-

tunity in which to intervene, prior to the prodrome.3

The present study

This report presents an extension and further analysis

of the childhood ratings of language and TD examined

by Ott et al. (2002). The study aims are three-fold : (1) to

further examine, with a substantially larger number of

participants, the suitability of TD as an indicator of a

schizophrenia diathesis ; (2) to compare the specificity

of different aspects of TD to SRP; and (3) to evaluate

the predictive validity of TD to SRP and more broadly

to psychosis. To date, few investigations have exam-

ined the predictive validity of TD in individuals prior

to the typical age of risk.# The notes appear after the main text.

2 D. C. Gooding et al.

Method

Participants

Participants were members of the two independent

samples of the NYHRP, each sample consisting of

offspring of schizophrenic, affectively ill and psychi-

atrically normal parents [high risk for schizophrenia

(HRSz), high risk for affective disorders (HRAff) and

normal control (NC) offspring groups, respectively].

All offspring were Caucasian, English speaking, and

free of mental retardation, major psychiatric disorders

or treatment for emotional problems at recruitment in

1971–72 (sample A) or 1977–79 (sample B) at ages 9.5

(S.D.=1.7) and 9.0 (S.D.=1.8) years, respectively.

Follow-up of both samples has included seven rounds

of examinations, approximately 3 years apart. Details

of the recruitment procedures, parental diagnoses,

and longitudinal follow-up have been presented else-

where (Erlenmeyer-Kimling et al. 1995, 1997, 2000).

After complete description of the study, written in-

formed consent was obtained from the parents for

themselves and their children starting at round 1 and

individually from the children who had reached age

18 years in subsequent rounds.

Assessment of TD

Speech samples for the TD ratings were obtained from

a videotaped semi-structured interview, which ques-

tioned the children about their family, friends, school

and leisure activities. The offspring interviews were

videotaped at regular intervals, beginning with round

1.4 The duration of the interviews ranged from 8 to

10 min.

TD was rated based on the Scale for TLC

(Andreasen, 1986), which can be used to quantitatively

rate manifestations of aberrant thought, language and

communication as they appear in spoken language.

This instrument provides a sufficiently broad range of

detailed symptom descriptions to permit rating of

subtle signs in individuals without overt symptoms,

as well as symptoms of TD frequently displayed by

individuals in the acute state of schizophrenia. The 18

TLC categories of aberrant communication can be

scored from 0 (no disorder) to 4 (extreme disorder) ;

see Andreasen (1986) for a complete description.

Higher scores indicate greater deviance.

Items from the TLC were combined to form three

subscales : global, negative and positive. The negative

TLC subscale score was the sum of the poverty

of speech and poverty of content of speech scores.

The positive TLC subscale score was the sum of the

tangentiality and the derailment scores. To calculate

the global subscale, scores for the more pathological

TLC symptoms (e.g. poverty of content of speech,

distractible speech, neologisms, incoherence) were

weighted prior to summing them with scores for the

less pathological TLC symptoms.

To investigate the factorial structure of the TLC

ratings, we performed principal components analyses

with orthogonal rotation. A two-factor solution dis-

tinguished positive and negative TD and explained

55% of the variance. From these factors, scales for

positive and negative TD were assembled and tested

for item-scale reliability. The resultant a reliabilities

for positive and negative TD were 0.85 and 0.65, re-

spectively.

Data reduction and derivation of TD factors

In this report, all available sample A data and sample

B data are pooled. A description of the training and

inter-rater agreement for sample A has been given

previously (Ott et al. 2002). The same two raters, who

remained naive as to parental diagnostic group and

adulthood diagnosis of the offspring, rated sample B

data. Estimation of inter-rater agreement for the total

sample was computed on a scale level, using the inter-

rater reliability of the mean (Winer et al. 1991).

Agreement was good for positive TD (0.83) and ac-

ceptable for negative TD (0.65).5

Assessment of outcome psychiatric diagnoses

In rounds 4 to 6, the Schedule for Affective Disorders

and Schizophrenia Lifetime Version (SADS-L;

Endicott & Spitzer, 1978) was administered to all par-

ticipants aged 18 years and older by trained clinical

psychologists and psychiatric social workers naive to

parental diagnostic group and offspring outcome di-

agnoses to assess Axis I disorders based on the

Research Diagnostic Criteria (RDC; Spitzer et al. 1978).

Final diagnostic evaluations were conducted in 2002,

at mean ages 39.4 (S.D.=1.8) years (sample A) and 34.1

(S.D.=2.3) years (sample B). Detailed descriptions of

the diagnostic evaluations have been given previously

(Erlenmeyer-Kimling et al. 1995, 1997, 2000). Briefly,

besides the SADS-L, the diagnostic evaluation in-

cluded all other clinical data : research interviews,

psychiatric hospital records, and when relevant,

therapists ’ notes and comments.

Adulthood Axis I disorders were categorized ac-

cording to the following hierarchy : (a) SRPs (including

schizophrenia, unspecified functional psychosis, and

schizo-affective disorder, mainly schizophrenia, as

defined in the RDC) ; (b) affective psychosis (psychotic

major depression, bipolar I with psychosis, bipolar II

with psychosis, manic psychosis, and schizo-affective

disorder, mainly affective, as defined in the RDC);

(c) non-psychotic affective disorders ; (d) other major

Thought disorder in childhood as a predictor of adulthood diagnosis 3

Axis I disorders (e.g. anxiety disorders, substance-

abuse disorders) ; (e) drug-related psychosis ; and ( f )

no disorder. Participants were also evaluated for the

presence of schizotypal features using the Personality

Disorders Examination (PDE; Loranger et al. 1987), a

semi-structured clinical interview designed to assess

all Diagnostic and Statistical Manual of Mental

Disorders, Third Edition, Revised (DSM-III-R) Axis II

disorders. The diagnostic algorithm provided in the

PDE was used (Squires-Wheeler et al. 1993).

Statistical analysis and study hypotheses

One of the goals was to determine whether subjects

with adulthood diagnoses of SRP or affective psy-

choses displayed specific aspects of elevated thought,

language and communication disturbances in child-

hood. General linear model multivariate analyses of

variance (MANOVA; SPSS version 19, SPSS Inc., USA)

were used to conduct the group comparisons with

parental risk and adulthood outcome diagnosis as the

independent variables. The main dependent variables

were the scales for TD (namely, positive, negative and

global TD). As the TLC data were non-normally dis-

tributed, they were transformed to z scores to nor-

malize the skewness of the scale scores. MANOVA

and univariate analyses of variance were performed

on the transformed scores. Group means for the TLC

variables are reported here using the untransformed

scores for ease of interpretation. To rule out the

possibility of increased TD being attributable to an al-

ready incipient psychosis, a correlation was computed

between level of TD and length of time elapsed be-

tween the interview and the onset of psychosis in the

23 subjects who later had a psychotic episode.

Logistic regression was used to determine whether

the presence of TD in mid-childhood was predictive

of an adulthood diagnostic outcome of SRP and

psychosis generally, including affective psychoses.6

Based on the literature on schizophrenia symptoms,

we hypothesized that certain aspects of TLC dis-

order – namely, negative TD – represented the ex-

pression of an underlying schizophrenia diathesis, i.e.

schizotypy. The relationship between schizotypal fea-

tures (derived from the PDE) and TD was assessed

with Pearson product moment correlations. Because of

the directional a priori hypotheses regarding the re-

lationship between schizotypal features and TD, one-

tailed tests were applied.

Results

Both usable videotaped interviews in mid-childhood

and diagnostic interviews in late adolescence/early

adulthood were available for 265 offspring: 74 in-

dividuals were genetically high risk for schizophrenia

(HRSz), 61 individuals were genetically high risk for

affective disorder (HRAff), and 130 were normal con-

trols (NC).7 The mean age of all participants at the time

of videotaping was 9.4 (S.D.=2.0) years. Of these sub-

jects, 23 developed psychotic illness, either SRP or af-

fective psychoses at a mean age of 18.4 (S.D.=4.2)

years. Table 1 provides the distribution of participants

by parental risk and adulthood outcome diagnosis.

TD as a function of parental risk and adulthood

outcome diagnosis

A MANOVA was run with dependent and indepen-

dent variables previously described, with full-scale

intelligence quotient (IQ) and socio-economic status

included to rule out possible confounding effects on

TD. The Wilks’ lambda multivariate test of overall

differences among groups was statistically significant

(p<0.01). The multivariate F was significant for the

main effect of IQ (F3,243=4.72, p=0.003) and adulthood

Table 1. Frequency of participants by parental risk and adulthood diagnostic outcome

Parental risk

Adult diagnostic outcome HRSz HRAff NC Total

Schizophrenia-related psychosis 10 (13.5) 4 (6.6) 0 (0) 14

Affective psychoses 5 (6.8) 3 (4.9) 1 (0.7) 9

Major affective disorders 23 (31.1) 31 (50.8) 43 (33.1) 97

Other Axis I/no disorder 36 (48.6) 23 (37.7) 86 (66.2) 145

Total 74 61 130 265

HRSz, High risk for schizophrenia ; HRAff, high risk for affective disorders ; NC,

normal controls.

Data are given as frequency of participants by parental risk group and adulthood

diagnostic outcome (percentage of parental group).


outcome diagnosis (F9,592=9.23, p<0.001), but not sig-

nificant for the main effect of parental risk (F6,488=1.45,

p=0.19). Notably, the main interaction between

parental risk and adulthood outcome diagnosis was

significant (F15,671=3.32, p<0.001), highlighting that

having a psychiatrically ill parent confers genetic risk

for a related psychiatric disorder.

Univariate between-subjects tests revealed that

adulthood diagnostic outcome was significantly, but

moderately, related to ratings of positive, negative and

global TD (all p’s <0.001 ; partial g2=0.12, 0.08 and

0.09, respectively). There was also a significant inter-

action effect between parental risk and adulthood

outcome diagnosis for positive TD (p=0.002 ; partial

g2=0.07). Means of TD ratings by parental risk and

adulthood diagnosis are presented in Table 2 and also

depicted in Figs. 1 and 2.8

Planned follow-up comparisons showed that sub-

jects with a psychotic diagnostic outcome (either SRP

or affective psychoses) were significantly higher in

positive TD than either of the two groups without

psychosis (p<0.01). However, the two psychotic

groups did not differ in terms of the positive TD rat-

ings (p=0.49). Overall, nearly 25% (65 of 265) of

the subjects showed any negative TD during mid-

childhood, with 45.9%, 23% and 13.1% in the HRSz,

HRAff and NC groups, respectively. A comparison of

the groups showed significantly higher negative TD

ratings in the SRP group than any of the other diag-

nostic outcome groups (p<0.001). Subjects with SRP

also displayed significantly higher levels of global TD

than the other three groups (p=0.001). Follow-up

comparisons of the interaction between parental risk

and the adulthood psychiatric classification of the off-

spring showed higher TD levels in SRP subjects than

the HRAff group overall, although this was significant

only for positive TD (see Table 2).

Tests of between-subjects effects indicated that full-

scale IQ was significant though weak for the positive

and negative TD scales, as demonstrated by their

partial g2 (0.017 and 0.016, respectively). The effect size

for the relationship between IQ and global TD was

somewhat stronger, with partial g2=0.046.

The appearance of TD before onset of psychosis

The 23 participants who developed psychosis had a

mean age of 10 (S.D.=2.2) years when their interviews

were taped. Their mean age at psychosis onset was

18.5 (S.D.=4.3) years. Therefore, the average length of

elapsed time was 8.23 years (range 4–19 years). A

Pearson product-moment correlation was computed

for the amount of time elapsed and the TD subscale

scores. These correlations with negative, positive and

global TD scales were low (r’s ranged from x0.03 to

0.14) and not significant (p’s ranged from 0.52 to 0.88).

Thus, high levels of TD in mid-childhood cannot be

attributed to imminent psychosis.

The association between schizotypal features and

formal TD9

Personality disorder symptom ratings for individuals

in the subsample ranged from 0 to 8 ; a minimum rat-

ing of 5 was required to meet diagnostic criteria for

schizotypal personality disorder. Zero-order Pearson

product-moment correlation coefficients were com-

puted between the PDE-derived ratings of schizotypal

features and the TD measures,10 yielding significant

values for all three scores : negative TD scores=0.12

(p=0.030), positive TD=0.18 (p=0.003) and global

TD=0.17 (p=0.005) (all p-values one-tailed). Thus,

increased schizotypal features were associated with

increased TD.

Prediction of SRP outcome

Logistic regressions were conducted to test a model

that predicted the presence or absence of a SRP out-

come. These analyses revealed that being a member of

the HRSz group, i.e. having a parent with schizo-

phrenia, rendered an individual’s risk 2.08 times

greater than other NYHRP subjects for developing

SRP in adulthood. An expanded model that took

positive TD ratings into account improved prediction;

consideration of negative TD over and above the other

Table 2. Means of thought disorder by parental risk and

adulthood diagnosis

Adulthood outcome diagnosis

Parental risk

HRSz HRAff NC

Positive thought disorder

Schizophrenia-related psychoses 0.80 2.00 –

Affective psychoses 1.00 0.50 0.00

Major affective disorders 0.48 0.26 0.08

Other Axis I/no disorder 0.14 0.07 0.02

Negative thought disorder





Global thought disorder





HRSz, High risk for schizophrenia ; HRAff, high risk for

affective disorders ; NC, normal controls.


variables resulted in still better prediction. The model

including all three variables appears in the upper half

of Table 3. With a 0.5 cut-off probability (i.e. a 50%

likelihood of developing a schizophrenia-related dis-

order), the model correctly predicted 94% of the sam-

ple. However, this probability value was unrealistic,

given the nature of the disorders we were trying to

predict and their low population base rates.

Based on a predicted cut-off probability value of

0.01, the model showed moderately high sensitivity,

with 64.3% (nine of 14) subjects being correctly pre-

dicted to develop SRP in adulthood; this group of nine

true positives included seven HRSz and two HRAff

subjects. However, the relatively high number of false-

negative cases who were missed by the model (i.e.

those who developed SRP but were not predicted to

do so) resulted in a lowered positive predictive value

(PPV; 40.9%). This group of five false negatives in-

cluded three HRSz and two HRAff subjects. Specificity

was high, with 94.8% of the subjects not at risk for the

later development of SRP being accurately predicted

by the model, as was the negative predictive value

(NPV) for the model, with an 89.8% probability that a

subject would not develop SRP in adulthood if they

2.01.81.61.41.21.00.8

TLC

rat

ings

0.60.40.2

0

TD by diagnostic outcome

Positive TD Negative TD

Other Axis I Dx/no Dx

Schiz-related psychoses Affective psychoses

Major affective Dx

Fig. 1. Group comparison of ratings by the Scale for the Assessment of Thought, Language, and Communication (TLC;

Andreasen, 1979) for positive thought disorder (TD) and negative TD by adulthood outcome diagnosis. Values are means, with

standard errors represented by vertical bars. See the Methods section for a description of symptoms that defined each subtype of

TD. Schiz, Schizophrenia ; Dx, disorder.

Glo

bal r

atin

g of

TD

in m

id-c

hild

hood

8

7

6

5

4

3

2

1

0Other Axis I/no

diagnosisSchiz-related

psychosisAffective psychosis

Major affectivedisorder

Adulthood diagnostic outcome

Fig. 2. Group comparison of ratings for global thought disorder (TD) by adulthood outcome diagnosis. Values are means, with

standard errors represented by vertical bars. For the calculation of the global TD rating, scores for the more pathological Scale for

the Assessment of Thought, Language, and Communication (TLC; Andreasen, 1979) symptoms were weighted prior to

summing them with the scores for the less pathological symptoms. See the Methods section for further description. Schiz,

Schizophrenia.


were not in the HRSz group and did not display high

ratings of positive and negative TD.

A model is presented in the lower half of Table 3,

which used global TD ratings as an alternative means

of predicting the later development of SRP. According

to this model, having a schizophrenic parent rendered

an individual at 3.04 times greater risk than other

NYHRP subjects for developing SRP in adulthood.

With a predicted cut-off probability value of 0.01, the

model based upon global TD ratings accurately pre-

dicted 12 of the 14 subjects (85.7%) who later devel-

oped SRP; the two subjects missed by this model were

both from the HRAff group. The model accurately

predicted 80.9% (203 of 251) of the subjects who did

not develop SRP. This model, therefore, showed high

sensitivity (86%) and relatively high specificity (81%).

Although the PPV for this model was low (20%), this

cut-off yielded a very high NPV (99%).

Discussion

One goal of this investigation was to evaluate TD as an

endophenotype of schizophrenia in confirmation of

the preliminary report by Ott et al. (2002). A second

goal was to evaluate TD as a potential predictor of

adulthood SRP. Previous work using a subset of

NYHRP sample A (n=123; Ott et al. 2002) had shown

that negative TD was related to SRP, independent of

parental risk. However, those analyses did not indi-

cate whether the relationship with negative TD re-

flected a specific association with schizotypy, rather

than a more general association with psychosis. With

the larger sample (n=265), we were able to analyse the

data such that comparisons could be made between

SRP and affective psychoses.

Numerous observations of positive TD in both af-

fective psychoses and SRP have been reported

for adolescents (Makowski et al. 1997) and

adults (Andreasen, 1979; Andreasen & Grove, 1986 ;

Holzman et al. 1986 ; Shenton et al. 1987 ; Solovay et al.

1987 ; Cuesta & Peralta, 2011). Consistent with those

findings, no difference was seen between the SRP and

affective psychoses subgroups with respect to positive

TD. Both subgroups displayed significantly greater

positive TD than participants without a psychotic

diagnostic outcome.

Negative TD, including poverty of content of

speech and verbal underproductivity, is associated

with schizophrenia in the general population

(Andreasen, 1979; Levy et al. 2010). As noted earlier,

negative TD is state independent, i.e. it manifests in

an individual whether or not illness is active.

Importantly, our research shows that negative TD is a

trait-like risk factor that presents by mid-childhood,

long before onset of psychosis in individuals who will

develop psychosis.

In contrast to positive TD, negative TD significantly

differentiated between diagnostic outcomes of SRP

and affective psychoses, with negative aspects of TD

being especially associated with risk to the develop-

ment of SRP. Additionally, we observed a small but

significant association of childhood TD ratings with

schizotypal features, which are perhaps a more

proximal indicator of the underlying schizophrenia

diathesis (Meehl, 1962, 1989). Our research thus adds

to the amassing support for considering negative TD

as an endophenotypic indicator of that diathesis.

Because the interview-based assessments of TD

were carried out when the NYHRP participants were

in mid-childhood, on average 8 years prior to illness

Table 3. Logistic regression equations predicting presence or absence of schizophrenia-related psychoses outcome in adulthood

B S.E. Wald df Significance Exp(B)

Model with positive TD and

negative TD subscales

Full-scale IQ x0.035 0.023 2.396 1 0.122 0.966

HRSz 0.920 0.703 1.712 1 0.191 2.510

Positive TD 0.484 0.231 4.394 1 0.036 1.623

Negative TD 0.616 0.212 8.441 1 0.004 1.852

Constant x0.584 2.406 0.059 1 0.808 0.558

Model with global TD subscale

Full-scale IQ x0.035 0.022 2.520 1 0.112 0.966

HRSz 1.113 0.682 2.661 1 0.103 3.043

Global TD 0.168 0.053 9.849 1 0.002 1.182

Constant x0.350 2.347 0.022 1 0.881 0.705

S.E., Standard error ; df, degrees of freedom; IQ, intelligence quotient ; HRSz, high risk for schizophrenia ; TD, thought

disorder.


onset, our findings point to TD as a long-standing,

enduring characteristic that precedes the manifes-

tation of clinical illness and, perhaps, even the prod-

rome.11

Our second goal was to determine whether TD in

mid-childhood has predictive validity for SRP in

adulthood. Logistic regression analysis confirmed that

parental risk predicts future SRP in combination with

mid-childhood TD and lowered IQ. These findings are

largely consistent with other investigations of in-

dividuals who later developed schizophrenia (Jones &

Done, 1997 ; Cannon et al. 2000) and/or schizophrenia-

spectrum disorders (Parnas et al. 1982).

Negative TD added to the prediction of SRP out-

comes over and above positive TD. Recently, prodro-

mal researchers have begun to consider the presence

of positive TD in their prediction of conversion to

psychosis. For example, Bearden et al. (2011) observed

that illogical thinking, one aspect of positive TD, pre-

dicted conversion to psychosis among prodromal

adolescents. To our knowledge, however, there are no

reports of any group attempting to apply ratings of

negative TD in their consideration of risk for psychosis

or SRP.

Both logistic regression models had high NPV.

Given the personal and societal costs of SRP, the more

important goal is to maximize the PPV to initiate

therapeutic intervention as early and as vigorously as

ethically possible. While the model with negative TD

considered separately from positive TD appears to

achieve this goal better than the model in which TD is

rated globally, neither model reached the generally

accepted cut-off of 80% PPV considered adequate for

clinical screening. Therefore, it may be premature to

consider either prediction model as adequate for

clinical application. Future directions include exam-

ination of these models combined with other potential

endophenotypes identified in the NYHRP.

A limitation of the investigation is that the sample is

entirely Caucasian. A sample more representative of

the general population would be desirable to enhance

the generalizability of the results. Additionally a larger

total sample overall with a greater yield of SRP and

psychotic affective outcomes would have been useful

for statistical power.

In summary, data from the NYHRP further eluci-

date the role of TD in relation to schizotypy. These

findings support consideration of TD as an endo-

phenotypic indicator of a schizophrenia diathesis. The

results demonstrate the predictive validity of positive

TD identified in childhood in relation to the later

development of psychosis. Most importantly, they

also demonstrate the specificity of negative TD to

predicting schizophrenia-related, but not affective,

psychoses.

Acknowledgements

The authors thank the participants in the study as well

as Ulla Hilldoff Adamo, M.A., for her work on the

project. The National Institute of Mental Health at the

National Institutes of Health (grant no. MH 19560-01-3

to L.E.-K.) and a University Sabbatical Research

Fellowship to D.C.G. supported the study.

Declaration of Interest

None.

Notes

1 The term ‘ formal thought disorder ’ refers to disturbances

or disruptions in the manner or mode of thinking, con-

centrating, attending or reasoning that include abnor-

malities associated with the relational and semantic

aspects of language (Solovay et al. 1987 ; Goldberg et al.

1998).2 For example, some investigations (Andreasen & Grove,

1986 ; Harvey et al. 1992) suggest that TD should be

broken down into two broad factors (e.g. verbal

productivity-disconnectivity), while others provide co-

gent findings in favor of two (negative v. positive ;

Andreasen, 1979) or three more specific (negative, posi-

tive and disorganization) factors.3 Unfortunately, the subsample of participants who were

interviewed (and therefore received TLC ratings) were

not wholly overlapping with those who were later ad-

ministered the Rorschach. Therefore, the samples are not

directly comparable.4 Some participants from sample A at round 1 are missing

videotaped interviews due to technical difficulties.5 While the reliability of the mean ratings for negative TD

is less than optimal, it is acceptable for use as a dependent

variable in analyses of variance models when comparing

group means rather than explaining individual differ-

ences.6 Because logistic regression does not require normally

distributed variables and does not assume homo-

scedasticity, non-transformed scores were used in these

analyses.7 The gender breakdown was as follows : HRSz, 42 males,

32 females ; HRAff, 22 males, 39 females ; NC, 77 males, 53

females.8 Raw scores are presented in Table 2 to ease interpretation.9 We were interested in examining the association between

schizotypal features and formal TD. Individuals with a

diagnosis of psychosis were excluded from this analysis,

and interview-based schizotypal ratings were unavail-

able for five additional subjects from the NC group.

Therefore, the analyses of schizotypal features and TD

are based upon 215 of 232 individuals (93% of the

sample).10 The sample n for this analysis is 230 ; in addition to

missing data, participants who had developed psychosis


by the time of this assessment were removed from the

analysis.11 As Kendler & Neale (2010) have elegantly delineated,

there are different models for endophenotypes. At pres-

ent, it is unclear whether negative TD may satisfy the

more stringent criteria for the mediational model (i.e.

whether genetic risk for schizophrenia passes through the

TD) as well as the criteria for a liability-index (or

‘ risk indicator ’) model. If the former case is true, then

negative TDmay be a pleiotropic expression of a trait that

co-occurs with other expressions of schizotypy.

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