The New England Family Study High-Risk Project:
Neurological Impairments Among Offspring of
Parents With Schizophrenia and Other Psychoses
Stephen L. Buka,1* Larry J. Seidman,2,3Ming T. Tsuang,3,4and Jill M. Goldstein2,3,5,6,7
1Department of Epidemiology, Brown University, Providence, Rhode Island
2Division of Psychiatric Neuroscience, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
3Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center (BIDMC),
Harvard Medical School, Boston, Massachusetts
4Department of Psychiatry, Center for Behavior Genomics, University of California at San Diego, San Diego, California
5Division of Women’s Health, Connors Center for Women’s Health and Gender Biology, Boston, Massachusetts
6BWH Department of Psychiatry, Boston, Massachusetts
7Harvard Medical School, Brigham and Women’s Hospital (BWH), Boston, Massachusetts
Manuscript Received: 15 April 2013; Manuscript Accepted: 12 June 2013
This manuscript presents the design and initial outcomes of
the New England Family Study’s (NEFS) High-Risk Project, one
of the few epidemiologically representative cohorts that has
prospectively followed a large sample of offspring of parents
with both affective and non-affective psychotic disorders from
the fetal period forward. The goals of this report are: (1) to
describe in some detail the design, data collection methods, and
and compare rates of childhood neurological impairments
among offspring of psychotic and nonpsychotic parents, with
a particular emphasis on offspring risk in relation to specific
classes of parental psychosis (i.e., affective vs. non-affective
psychosis). The investigators identified a pool of 755 parents
confirmed psychotic diagnoses for 212 affected parents and 132
with psychosis had approximately a twofold increased risk of
abnormal neurological functioning compared to offspring of
families with no psychotic history. This was most pronounced
among the 58 offspring of parents with schizophrenia. Similar
reach statistical significance. Neither at birth nor at any of the
follow-up assessments were the 157 offspring of parents with
affective psychosis found to be at elevated risk of neurological
impairment. Implications for future research and potential
preventive interventions for at-risk individuals are discussed.
? 2013 Wiley Periodicals, Inc.
Key words: epidemiology; psychosis; etiology; risk factors;
High-risk (HR) studies have proven invaluable over the past
50 years to advance understanding of the biological and social
origins and course of schizophrenia and other psychotic disorders
[Niemi et al., 2003; Cunningham Owens and Johnstone, 2006].
Alternative designs, such as cohort and conscript studies, are
disorders in the general population, necessitating a large sample of
premorbid assessments prior to the onset of later psychotic dis-
disorder [Cornblatt and Obuchowski, 1997]—require smaller
sample sizes and allow a wider range of methods to be employed
because of reduced expense in sampling. Specifically, the ability to
How to Cite this Article:
Buka SL, Seidman LJ, Tsuang MT,
Goldstein JM. 2013. The New England
Family Study High-Risk Project:
Neurological Impairments Among
Offspring of Parents With Schizophrenia
and Other Psychoses.
Am J Med Genet Part B 162B:653–660.
Stephen L. Buka, Sc.D., Department of Epidemiology, Brown University,
121 South Main Street, Providence, RI 02810.
Article first published online in Wiley Online Library
? 2013 Wiley Periodicals, Inc.
birth) who are at elevated risk of developing schizophrenia later in
life owing to an ill family member, usually parents or siblings,
(“family HR” or “genetic HR” design) has supplemented the work
ments of premorbid conditions.
Prior family high-risk (FHR) studies have generally supported
the idea of parental mental illness as a substantial risk factor for
atypical child development and adjustment. This is especially true
for parental psychotic disorders [Hans et al., 2004; Johnstone
rates and greater severity of neurological, motor, and cognitive
impairments among offspring of parents with schizophrenia
compared to offspring of unaffected parents, including infants
[Sameroff et al., 1984; Blennow and McNeil, 1991], younger
children [Rieder and Nichols, 1979; Auerbach et al., 1993; McNeil
McNeil, 2004; Seidman et al., 2006]. Regarding neurological func-
[Marcus et al., 1985] and the Jerusalem Infant Development Study
[Hans et al., 1999] reported higher rates among HR offspring.
Marcus et al.  found that offspring of parents with schizo-
phrenia had significantly greater deficits in motor coordination,
sensory-perceptual signs, and balance. These offspring also exhib-
ited poor right-left orientation and motor overflow. Hans et al.
of 24 offspring of parents with schizophrenia and 16 offspring of
unaffected control parents. Among the HR offspring, 42% exhib-
ited impaired neurobehavioral functioning (based on motor and
cognitive-attentional variables) compared to 4% of the unaffected
Less is known about the neurological development of offspring
of parents with affective psychosis in comparison to offspring of
[McNeil et al., 1993] examined a series of neuromotor behaviors
and “different facets of general mental development” in relation to
the general class of parental psychosis. These authors reported that
summary neuromotor deviation scores were significantly higher
control offspring (P ¼ 0.027), but not so for offspring of mothers
with affective psychoses and their matched controls. In particular,
offspring of mothers with schizophrenia had significantly lower
scoresonlocomotor(P ? 0.001)andeye-hand(P ? 0.005)meas-
ures (reflecting gross and fine motor performance) than their
matched controls, differences that were not observed among off-
spring of mothers with affective psychoses. The results of the study
suggested that neuromotor deficits are specific to offspring at HR
for schizophrenia as offspring among mothers with affective psy-
choses did not exhibit similar deviations relative to their controls.
In contrast, the Helsinki High-Risk Study examined childhood
(age 7–17) neurological soft signs (e.g., “with tics or subthreshold
hypotony) in 159 high risk and 99 control offspring [Niemi
with affective psychosis exhibited neurological soft signs. The rate
of neurological soft signswassignificantly greateramong offspring
of mothers with affective psychosis (P ¼ 0.0006)—but not in
offspring of mothers with schizophrenia—compared to offspring
of healthy control parents. Thus, while prior work tends to suggest
more neurological abnormalities in HR offspring of parents with
theNewEngland Family Study’s(NEFS)High-RiskProject,one of
the few epidemiologically representative cohorts that has prospec-
tively followed a large sample of HR offspring of parents with both
forward. The goals of this report are: (1) to describe in some detail
the design, data collection methods, and resulting sample of the
NEFS HR Project; and (2) to prospectively identify and compare
rates of childhood neurological impairments among offspring of
offspring risk in relation to specific classes of parental psychosis
(i.e., affective vs. non-affective psychosis).
Participants for this study were selected from the Providence, RI
and Boston, MA cohorts of the Collaborative Perinatal Project
(CPP) of the National Institute of Neurological and Communica-
tive Disorders and Stroke [Niswander and Gordon, 1972], also
known as the NEFS. Pregnant women who were receiving prenatal
care at 1 of 12 participating university medical centers were
recruited into the CPP study between 1959 and 1966. From the
Providence and Boston sites, 17,741 pregnancies (13,464 mothers)
and the neonatal period were systematically assessed. Children’s
mental, motor, sensory, and physical development were also
assessed at 4 and 8 months and 1, 4, and 7 years of age. We refer
to the pregnant women and their partners as “Generation 1”or G1
and the study offspring as Generation 2 (G2), following the
terminology of Hardy et al. .
Identifying G1 parents with major potential psychotic disorders.
We attempted to identify all G1 participants with a history of
psychiatric treatment and/or hospitalization (Fig. 1). In a previous
families in which either one or both parents had psychiatric
diagnoses: 71 had definite psychosis; 46 had possible psychosis;
and 37 had other nonpsychotic diagnoses. The 117 families (66
mothers; 51 fathers) with either definite or possible psychosis were
included in the potential sample for this study. Subsequent record
al 437 G1 parents who had received psychiatric treatment and/or
alinkage diagnosisofeitherpsychosisorbipolardisorder andwere
included in the potential sample for this study.
Parents with ahistoryofpsychiatric treatment and/orhospitali-
zation were identified at various times in the original CPP study
(total n ¼ 1,076). At study enrollment, all of the women were
asked: (1) “have you ever been a patient in a psychiatric hospital?”
and (2) “has the father of this baby ever been a patient in a
psychiatric hospital?” Maternal and paternal history of outpatient
treatment and treatment for drug or alcohol addiction was also
recorded. 164 parents (65 mothers and 99 fathers) had reports of
654 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
were asked “has anyone in this child’s family been treated for a
psychiatric condition?” At this assessment, 907 families reported
maternal (n ¼ 556), paternal (n ¼ 184), or some combination of
family member (n ¼ 167) psychiatric treatment and five mothers
were included because they reported having taken anti-psychotic
medications at the baseline assessment. Chart notes were reviewed
for all of these and a total of 518 G1 parents included in the fielded
In recent follow-up studies with the CPP cohort, there were 22
a history of psychiatric treatment and/or hospitalization or a
psychotic diagnosis—these were included in the potential study
sample. Finally, based on interviews with a randomly selected
sample of potential control subjects, we identified 25 G1 parents
who reported psychiatric hospitalization,of which 12 were includ-
ed in the potential case sample based on review of interview notes.
From these sources, a total of 859 parents were identified with a
history of psychiatric treatment and/or hospitalization and whom
had some potential indication of a probable or possible psychotic
eligible for follow-up in the original CPP (i.e., child was stillborn,
aborted, not seen past birth, or adopted away from the project),
were initiated for 755 participants (Fig. 2).
Diagnostic procedures. Located participants were invited to
interview assessed sociodemographic characteristics, medical his-
tory, developmental history (e.g., schooling, educational or learn-
ing problems, head injuries), and screened for psychiatric
symptomatology. Psychiatric symptomatology was assessed using
the Quick Diagnostic Interview Schedule [Robins et al., 1989] to
screen for Axis I disorders. The Personality Dimensions Question-
naire [Hyler, 1990] was used to screen for Cluster A, Axis II
personality disorders (i.e., schizotypal, schizoid, and paranoid
personality disorders). Participants were also asked to sign releases
for medical records for psychiatric hospitalizations and outpatient
treatment. This interview was conducted by systematically trained
Bachelor’s-level research assistants and then reviewed by four
expert doctoral-level diagnosticians to determine whether there
was sufficient evidence to indicate potential psychosis and thus to
warrant a second interview.
The second interview used the Structured Clinical Interview
for Diagnosis (DSM-IV: SCID [First et al., 1996]) and yielded
Axis I diagnoses of any form of psychotic, major affective,
bipolar or substance use disorders. Family history of psychiatric
disorders was evaluated using the Family Interview for Genetic
Studies [Maxwell, 1996]. The expert diagnosticians reviewed
all of the information collected from both interviews and
medical records1, if available, to determine final best estimate
Selection criteria for parents without a history of psychiatric
treatment. Once a potential HR parent was identified, matched
control parents were selected to be comparable on the following
characteristics: number of offspring enrolled in the CPP;
patient insurance status (public or private); parent age; ethnicity
FIG. 1. Summary of sources for pool of potential G1 parents with a psychotic disorder.
1Diagnosticians reviewed diagnostic information for 500 participants.
Of these reviewed participants, the following types of data were
available: 62% interview only; 20% interview and medical records; 18%
record linkage diagnosis only.
BUKA ET AL.
chronic fetal hypoxia. We sought a comparable proportion of
comparison offspring with a history of chronic hypoxia to maxi-
mize statistical power toexaminethe independent andjoint effects
of parental diagnosis and this perinatal risk factor. Offspring were
rated positive for a history of chronic perinatal hypoxia if prenatal
records indicated one or more of the following: mild to severe
preeclampsia; maternal hypertension (diastolic blood pressure
during pregnancy of 95 mmHg or greater); maternal hypotension
or gestational diabetes (based on insulin therapy, insulin reaction,
or blood sugar 200 mg or greater during pregnancy). Eligible
controls included all members of the CPP who were not identified
history of psychiatric treatment. A mix of potential cases and
controls were released for fieldwork to ensure that interviewers
were blind to G1 diagnostic status. If the potential control was
interviewed and determined to be ineligible as a control, then a
replacement control was released. Interviewers remained blind to
potential diagnostic status. All human subject activities were
reviewed and approved by multiple Institutional Review Boards
at Harvard University and participating hospitals.
Exclusion criteria for the sample of unaffected control G1
parents were the following: history of psychiatric hospitalization;
Axis I psychotic disorders; bipolar disorder; recurrent major de-
pression without psychotic features; Axis II Cluster A personality
disorders; or genetic disorder with known neurobiological deficits
(e.g., Huntington’s disease). Unaffected G1 parents were also
excluded if there was evidence of psychosis, mania, suicide, or
genetic disorder with known neurobiological deficits among their
FIG. 2. Study eligibility and participation: Summary information.
656 AMERICAN JOURNAL OF MEDICAL GENETICS PART B
siblings or parents. Figures 1 and 2 document these sampling
procedures in detail.
among the G2 offspring. Family socioeconomic status (SES) aver-
aged the percentile scores of parents’ education, occupation, and
income [Myrianthopoulos and French, 1968]. Maternal race was
basedon G1maternalself-report asCaucasian orother. Neurolog-
ical assessments of G2 offspring were conducted though physician
examination at birth, at 1 and 7 years to screen for possible
nervous and other body systems. Based on the examination, an
cal impairment. For the current analyses, the categories of “possi-
ble” and “certain” neurological impairment were combined.
ing procedures were used to estimate the odds of neurological
accounted for multiple children per family. Rates of neurological
impairments among G2 offspring were examined based on assess-
considered rates of impairments for all time points combined.
Study Sample and Completion Rates
in a sample of 212 parents with DSM-IV psychotic disorders (153
mothers and 59 fathers). This included 84 parents with non-
affective psychoses (59 with schizophrenia; 1 with schizophreni-
otherwise specified); 20 with schizoaffective disorder (11 with
depressed type; 9 with bipolar type); 96 with affective psychoses
including bipolar disorder (n ¼ 48) or major depressive disorder
(MDD) with psychosis (n ¼ 48). Based on past literature on
familial transmission of schizophrenia and affective psychoses
[Faraone and Tsuang, 1985; Kendler et al., 1985; Tsuang, 1993],
parents with schizophrenia, schizoaffective disorder of depressed
type, delusional disorder, brief psychosis, schizophreniform disor-
(schizophrenia psychosis spectrum disorders, subsequently re-
ferred to as SPS), and schizoaffective disorder of bipolar type,
bipolar disorders with psychosis, and MDD with psychosis were
classified into a second group (affective psychoses, subsequently
referred to as AP). Twelve parents with a history of psychotic
diagnosis which was brief compared to other psychiatric disorders
(e.g., major depression or substance disorders) were also included
inthesetwopsychoticgroups(n ¼ 11intheaffectivegroup;n ¼ 1
in the non-affective group). For 57 subjects, diagnoses were based
upon hospital chart information only. In the four instances where
certainty of a psychotic diagnosis was chosen. This resulted in a
sample of116 parents diagnosedwithaffectiveand 92parents with
non-affective psychotic disorders.
A sample of 308 parents without a history of psychiatric treat-
ment was identified as potential controls (268 mothers and
40 fathers). Of these, 12 parents were determined to have had a
history of psychotic illness and six were not attempted for follow-
and 45 of these (17%) refused participation. Based on exclusion
criteria detailed above, a final sample of 132 parents (119 mothers
and 13 fathers) without psychiatric history were included in the
unaffected G1 parent group.
HR samples, including comparisons of participants with different
types of psychoses. Significant differences emerged in (a) the
number of children per family, where families with a history of
schizophrenia or any non-affective psychosis tended to have fewer
children than unaffected families, (b) family SES, where families
with history of any non-affective psychosis tended to have lower
SES than unaffected families, and (c) maternal age at study entry,
to be younger than unaffected mothers.
Offspring sample. The final sample of 208 families with and
132 families without a psychiatric history had a total of 467
pregnancies enrolled in the CPP (167 offspring of parents with
affective psychoses, 114 offspring of parents with non-affective
psychoses; and 186 offspring of unaffected parents).
Neurological data were available for 434 offspring at birth; for
408 at 1 year; and for 409 at 7 years of age. As a result, 93% of the
sample had at least one, and 77.1% had all three neurological
assessments. Families with a history of any psychotic disorder
were equally likely as control families to have at least one valid
Neurological impairment among offspring of parents with
psychotic disorder. Table II presents the rates of abnormal neu-
rological assessments relative to parental diagnostic group. When
considering all assessments simultaneously (“overall results”),
offspring of parents with schizophrenia were observed to have a
significantly elevated risk of abnormal neurological functioning
comparedtotheoffspringofunaffectedparents(oddsratio ¼ 1.98;
95% confidence interval 1.05–3.71). This relative risk was non-
non-affective psychoses (OR ¼ 1.63; P ¼ 0.08) and offspring of
parents with affective psychoses (OR ¼ 1.44; P ¼ 0.12), and as a
consequence among the offspring of all psychoses combined (OR
¼ 1.51; P ¼ 0.06). For both the neonatal and age 7 year assess-
impairment were greatest among the offspring of parents with
schizophrenia, followed by offspring of any non-affective psycho-
ses, any affective psychoses and lowest among low-risk offspring.
temporal patterning of neurological impairments (persistent, late
occurring only, early occurring only) revealed no clear relation to
BUKA ET AL.
This report provides a detailed summary of the design, assessment
HR Project, initiated by Prof. Ming Tsuang. The utility of the HR
design was demonstrated through examination of a simple yet
important question: are offspring of parents with psychosis (and
certain classes of psychoses) at elevated risk for early neurological
impairments? We report that offspring of affected parents were at
elevated risk,withsuchimpairmentsmostpronounced atbirth.At
birth, HR offspring had approximately a twofold increased risk of
lies with no psychotic history. This was most pronounced among
offspring of parents with schizophrenia: almost 20% of children
from this group exhibited some neurological dysfunction at birth
at birth nor at any of the follow-up assessments were offspring of
parents with affective psychosis found to be at elevated risk of
neurological impairment. While these differences were in the
expected direction at the 1 and 7 year assessments, the results
did not reach statistical significance. However, when the entire
developmental period was examined (birth through 7 years), the
results were consistent with the neonatal assessment and elevated
odds were observed in relation to parental psychosis (especially
These results are consistent with prior reports on neurological
functioning among offspring of parents with psychoses, in which
these problems were most prominent, (1) in children of more
severely afflicted parents (i.e., parents with schizophrenia as op-
posed to any other psychosis, or parents with chronic as opposed
to acute schizophrenia) [Rieder and Nichols, 1979; McNeil
et al., 1993]; and (2) at birth or in the first months of life, but
et al., 1985].
Early characterization of neurological impairments in children
of parents with schizophrenia and other psychoses may help
identify those who may be at higher than usual risk for subsequent
disability. This could help target children who may need to be
followed through adolescence and young adulthood allowing for
early intervention, if for example, they developed school or neuro-
cognitive problems. Such difficulties may look superficially like a
cal or neuropsychological impairments may warrant different
interventions than standard.
psychosis are most likely to develop psychotic illness, the prior
presence of a history of neurological dysfunctions and family
history of psychosis may heighten clinical attention, particularly
old) positive symptoms [McGlashan and Johannessen, 1996].
These symptoms (“clinical high risk syndrome”) have been shown
years [Cannon et al., 2008]. It is not yet known to what extent the
presence of childhood neurological dysfunction may increase risk
high risk individuals who later convert to psychosis have more
severe neuropsychological impairment than non-converters and
severe neuropsychological impairment prior to onset of psychosis
project have reported on rates of psychotic disorders in adulthood
[Goldstein et al., 2010, 2011]. Consistent with previous high-risk
TABLE I. Characteristic of the Parent (N ¼ 340 Families) and Offspring (N ¼ 467) Samples
Unaffected Any psychosis
Parental characteristicsN ¼ 132
Family SES at study entry; M (SD) 5.7 (2.1)
Mother’s age at study entry; M (SD)27.1 (6.6)
CPP offspring in family; M (SD)1.4 (0.8)
G1 diagnostic groupAny AP
N ¼ 116
N ¼ 92
N ¼ 208N ¼ 57
N ¼ 186
N ¼ 281
N ¼ 167
N ¼ 114
N ¼ 68
AP, affective psychosis; NAP, non-affective psychosis; SCZ, schizophrenia.
(“lowest”) to 9.5 (“highest”).
Demographic characteristics of the control families and the psychotic families were compared; where
§P < 0.10.
?P < 0.05.
658AMERICAN JOURNAL OF MEDICAL GENETICS PART B
diagnostic criteria for a psychotic disorder, a fivefold increase
compared to the unaffected control sample. Subsequent analyses
will investigate the extent to which early neurological impairments
these and related longitudinal investigations, many stimulated by
the pioneering work of Dr. Ming Tsuang, we have entered a new
phase of early intervention and prevention of psychiatric disorders
[Insel, 2006]. As this work progresses, it will be important to
as we move in the direction of developing ethically acceptable
strategies of early detection and efficacious and non-harmful
prevention approaches [Cannon, 2005].
Work for this study was supported by NIMH RO1 MH50647
(1999–2003, Tsuang, P.I.; 2003–2006, Goldstein, P.I.), and the
like to express their appreciation to the dedicated NEFS research
team including Jasmina Burdzovic-Andreas, Ph.D.; Sara Cherker-
zian, Sc.D.,Lisa Denny, M.D.; Jo-Ann Donatelli, Ph.D.,Christiana
Provencal, M.A.; Anne Remington, M.A., and to the sustained
involvement and many contributions of the NEFS study
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TABLE II. Summary of GEE and Logistic Regression Analyses, Estimating Odds of Any Neurological Impairments Among Offspring of
Parents With Psychotic Illness Versus Unaffected Parents
n% ORP-value 95% CI
Any affective psychosis
Any non-affective psychosis
Any affective psychosis
Any non-affective psychosis
Year 1 assessment
Any affective psychosis
Any non-affective psychosis
Year 7 assessment
Any affective psychosis
Any non-affective psychosis
Shown are odds ratios adjusted for repeated assessments (for overall results), intra-familial correlation, family SES, and maternal age.
Any time ¼ child scored positive at any assessment versus scoring negative at all three.
aSignificant effect of family SES.
bSignificant effect of maternal age.
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