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ANOREXIA NERVOSA AND ANXIETY DISORDERS:
AN EXAMINATION OF COMORBIDITY AND
SHARED TRANSMISSION

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GILLIAN M. STAVRO

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ANOREXIA NERVOSA AND ANXIETY DISORDERS:
AN EXAMINATION OF COMORBIDITY AND SHARED TRANSMISSION
By

Gillian M. Stavro

A THESIS
Submitted to
Michigan State University
in partial fulﬁllment of the requirements
for the degree of
MASTER OF ARTS
Department of Psychology

2003

ABSTRACT

ANOREXIA NERVOSA AND ANXIETY DISORDERS:
AN EXAMINATION OF COMORBIDITY AND SHARED TRANSMISSION

By
Gillian M. Stavro

Objective: The current study sought to examine the nature of the relationship
between anorexia nervosa (AN) and anxiety disorders (AD). There were two aims: (1) to
examine comorbidity of AN and AD; and (2) to determine whether AN and AD share a
common diathesis by examining rates of eating and anxiety disorders in parents Of
probands with AN and AD. Method: Female probands were selected from the
Minnesota Twin and Family Study. To examine comorbidity, rates of AD were
compared between probands with AN (3 = 36) and probands with no eating pathology m
= 287). As well, frequencies Of eating and anxiety disorders were compared between
parents Of probands with AN (n = 31 moms, 27 dads), or an AD (n = 109 moms, 92
dads), and controls with no eating or anxiety disorders m = 43 moms, 41 dads) using chi-
square, prediction analysis, and Odds ratios. Results: Increased rates of comorbidity
were supported as probands with AN showed higher rates of anxiety disorders than
probands with no eating pathology. There was also support for shared transmission;
parents of probands with AN had increased rates Of both eating and anxiety disorders,
regardless Of anxiety comorbidity in probands. The same was found in parents Of
probands with multiple AD. Discussion: Initial support was provided for shared
transmission of eating and anxiety disorders. However, differences in rates Of
transmission across study groups indicate the need for future research to examine AN and

AD families to more precisely deﬁne etiologic relationships between the two phenotypes.

ACKNOWLEDGEMENTS

This study was supported by a grant from the Blue Cross and Blue Shield Foundation of
Michigan Student Award Program. I would like to say ‘thank you’ to Dr. Klump for
being so involved and helping me with all aspects of this manuscript. Many thanks as
well go to Dr. von Eye for his aid and advice. The time and effort you both provided was
greatly appreciated.

iii

TABLE OF CONTENTS

LIST OF TABLES ............................................................................................................. V
INTRODUCTION ............................................................................................................. 1
COMORBIDITY BETWEEN AN AND ANXIETY DISORDERS ................................................ 2
EVIDENCE FOR THE HERITABILITY OF AN ....................................................................... 5
EVIDENCE FOR THE HERITABILITY OF ANXIETY DISORDERS ............................................ 7
TRANSMISSION OF AN AND ANXIETY DISORDERS ........................................................... 8
STUDY OBJECTIVES ....................................................................................................... 14
Overall Purpose ......................................................................................................... 14
Speciﬁc Aims and Hypotheses ................................................................................. 15
METHOD ......................................................................................................................... 16
PARTICIPANTS ................................................................................................................ 16
MEASURES ..................................................................................................................... l9
DIAGNOan PROCEDURES ............................................................................................. 21
STATISTICAL ANALYSES ................................................................................................ 23
RESULTS ......................................................................................................................... 25
ANALYSIS 1: ExAMINING COMORBIDITY IN PROBAND SAMPLE ..................................... 25
ANALYSIS 2: EXAMINATION OF THE CROSS-TRANSMISSION OF EATING AND ANXIETY
DISORDERS. .................................................................................................................... 26
PROBAND STRATIFICATION ............................................................................................ 28
DISCUSSION ................................................................................................................... 30
COMORBIDITY OF EATING AND ANXIETY DISORDERS IN PROBANDS ............................. 30
CROSS-TRANSMISSION OF EATING AND ANXIETY DISORDERS ......................................... 32
MODELS OF COMORBIDITY ............................................................................................ 35
CONCLUSIONS AND STUDY LIMITATIONS ....................................................................... 36
REFERENCES ................................................................................................................. 40
APPENDIX ....................................................................................................................... 46

iv

LIST OF TABLES

Table 1: Lifetime rates of anxiety disorders among probands with anorexia nervosa and
control probands without eating pathology ....................................................................... 47

Table 2: T-test comparing mean scores on State Trait Anxiety Inventory (STAI)
subscales between probands with anorexia nervosa (AN) or no eating pathology
(Controls) .......................................................................................................................... 48

Table 3: T-test comparing mean scores on State Trait Anxiety Inventory (STAI)
subscales between probands with anorexia nervosa (AN), probands with anxiety, and
probands with no eating or anxiety diagnoses (Controls) ................................................. 49

Table 4: Rates Of individual eating and anxiety disorders in parents of probands with
AN, an anxiety disorder, or no eating or anxiety pathology (Controls) ........................... 50

Table 5: Comparison of rates of eating disorders (ED), anxiety disorders, and no eating
or anxiety pathology among parents of probands with anorexia nervosa (AN), an anxiety
disorder, or no eating or anxiety pathology (Controls) ..................................................... 51

Table 6: AN OVA comparing M-EDI and STAI—Trait subscale means between parents of
probands with anorexia nervosa (AN), an anxiety disorder, or no eating or anxiety
pathology (Controls) ......................................................................................................... 52

Table 7: Comparison Of rates of eating disorders (ED), anxiety disorders, and no eating
or anxiety pathology among parents of probands with anorexia nervosa (AN) only, both
AN and an anxiety disorder, one anxiety disorder, multiple anxiety disorders, or no eating
or anxiety pathology ......................................................................................................... 53

Table 8: ANOVA comparing M-EDI and STAI-T means between parents Of probands
with either anorexia nervosa (AN) only, AN and an anxiety disorder, an anxiety disorder,
or no eating or anxiety pathology (Controls) .................................................................... 54

Anorexia Nervosa and Anxiety Disorders:
An Examination of Comorbidity and Shared Transmission

Anorexia nervosa (AN) is a disorder Of unknown etiology which affects
approximately 0.5 - 1.0 % of adolescent and young women over their lifetime (Hock,
1993; Hsu, 1990). The protracted course Of the illness (Herzog et al., 1999; Strober,
Freeman, & Morrell, 1997), combined with a mortality rate greater than that Of any other
psychiatric disorder (Sullivan, 1995), makes it pertinent that research focus upon risk
factors involved in the development of AN. Traditionally, researchers have focused on
the intense social pressures for a thin ﬁgure in industrialized nations as the primary
contributing factor to the onset of AN (Garner, Garﬁnkel, Schwartz, & Thompson, 1980).
However, the great majority Of females that are exposed to these pervasive pressures
never develop AN. Therefore, it is apparent that there are other processes which
predispose certain women to develop AN (Chatoor, 1999).

Other potential risk factors, such as other forms of psychopathology, are currently
being investigated to determine if they contribute to the development of AN. The
increased rates of certain psychiatric disorders in women with AN has long been
recognized (Wonderlich & Mitchell, 1997). The most common comorbid disorders are
depressive and anxiety disorders (Toner, Garﬁnkel, & Garner, 1988; Fomari et al., 1992;
Herzog, Keller, Sachs, Yeh, & Lavori, 1992; Herzog, Nussbaum, & Marmor, 1996).
Historically, researchers have minimized the elevated rates Of anxiety disorders in order
to emphasize the link between eating and depressive disorders (Fornari et al., 1992;
Hudson, Harrison, Yurgelton-Todd, Jonas, & Frankenburg, 1987; Hudson, Pope, Jonas,

& Yurgelton-Todd, 1983). However, the nature of the relationship between eating and

depressive disorders remains elusive, as studies have provided conﬂicting information
regarding potential etiological associations (Strober, Lampert, Morrell, Burroughs, &
Jacobs, 1990; Wade, Bulik, Neale, & Kendlcr, 2000; Logue, Crowe, & Bean, 1989). On
the other hand, recent studies have suggested a common, genetically-mediated diathesis
between eating disorders (ED), phobias and panic disorder (Kendler et al., 1995), and a
similar association has been suggested for AN and childhood anxiety disorders (Keel,
Klump, Miller, McGue, & Iacono, in preparation). Such ﬁndings highlight the
potentially signiﬁcant role anxiety disorders play in the development and maintenance Of
AN, and thus underscore the importance Of examining these relationships further.
Comorbidity Between AN and Anxiety Disorders

The prevalence estimates for anxiety disorders in women with AN range widely,
but are consistently higher than those found in the general population. In one sample of
treatrnent-seeking women with restricting AN, 73% were diagnosed with a current
comorbid Axis I disorder at intake (Herzog et al., 1992); 20% of them were diagnosed
with a current anxiety disorder. Other studies assessing lifetime rates of anxiety have
found that 46% Of an outpatient sample (Fomari et al., 1992), and 35% (Braun, Sunday,
& Halmi, 1994), 60% (Bulik, Sullivan, Fear, & Joyce, 1997), and 83% (Godart, Flament,
Lecrubier, & J cammet, 2000) of inpatient AN samples have met criteria for at least one
anxiety disorder at Some point during their lifetime. It should be noted that only these
last two studies included childhood anxiety disorders, which may account for their higher
rates of lifetime comorbidity. Since the onset Of AN occurs in mid- to late-adolescence
for most women (American Psychiatric Association, 1994), the vast majority of eating

disorder patients have not yet passed through the period of risk for many adult anxiety

disorders, but have done so for the childhood disorders. Comorbidity studies which do
not assess the presence of childhood anxiety disorders are therefore likely to be
underestimating the true prevalence of lifetime anxiety disorders in women with AN.

One lirrritation of many Of these comorbidity studies that use clinic populations is
that comorbidity may be increased in subjects seeking treatment. Speciﬁcally, the
likelihood of treatment seeking has been found to be increased when more than one
disorder is present (Galbaud, Newman, & Bland, 1993). This Sampling bias makes it
difﬁcult to determine whether the same extent of comorbidity actually exists in the
general population. Nonetheless, population-based studies have found elevated rates of
anxiety disorders in women diagnosed with AN (Keel et al., in preparation; Walters &
Kendlcr, 1995), although rates have generally been lower than those Obtained in clinic-
referred samples. Consequently, the frequent co-occurrence of AN and anxiety disorders
seems to also exist in non-treatrnent seeking samples.

Another criticism levelled at studies of comorbidity in AN is that the behavioural
or affective symptoms of comorbid disorders may simply be secondary consequences of
malnourishment (Toner et al., 1988). The direct physiological effects of starvation
include increased depressive symptoms, nervousness and anxiety (Keys, 1948), thus the
symptoms of anxiety seen in women with AN may simply be due to starvation.
However, studies of long-term weight restored AN women have found lifetime rates Of
adult anxiety disorders of 47% (Toner et al., 1988) and 53% (Halmi et al., 1991), which
are still considerably higher than those expected in the general population. Further, 58%
of long-term recovered AN patients report having had a childhood anxiety disorder

(Deep, Nagy, Weltzin, Rao, & Kaye, 1995). Finally, almost half Of a sample of former

AN patients assessed seven years after they initially sought treatment met criteria for a
current anxiety disorder diagnosis (Herpertz-Dahlmann, Beate, Wewetzer, Schulz, &
Remschmidt, 1996). These results suggest that high rates of both lifetime as well as
current anxiety diagnoses are found in women with a history of AN even when
malnutrition is not present.

Another reason it is unlikely that symptoms of anxiety are simply manifestations
Of malnourishment is the ﬁnding that, in the majority of cases, the onset of the anxiety
disorder precedes the onset of AN. Twenty-three to 72% of women comorbid for AN
and an adult anxiety disorder report an earlier onset of the anxiety disorder (Braun et al.,
1994; Toner et al., 1988). Childhood anxiety disorders are reported to have an earlier
onset than AN in 79% of long-term recovered AN patients (Deep et al., 1995). When
both childhood and adult anxiety disorders are taken into account, the numbers are even
higher: 83% (Godart et al., 2000) to 90% (Bulik et a1. 1997) of anorexic women report an
antecedent onset of their anxiety disorder.

In summary, high rates of anxiety disorders are consistently found in women with
a primary diagnosis of AN. These elevated rates exist in both clinical and community
populations regardless of state of illness, often with the anxiety disorder developing prior
to AN. These stable, predictive relationships between eating and anxiety disorders
underscore the importance Of understanding the nature of the comorbid relationship.
Indeed, understanding this nature is likely to provide information about the development
and maintenance Of AN.

Comorbidity research, which was once mainly descriptive, is now attempting to

apply explanatory models in order to elucidate the etiological signiﬁcance of the co-

presentation of certain psychiatric disorders with AN (W onderlich & Mitchell, 1997).
Two speciﬁc models, and their respective variations, are supported by the research
reviewed on AN and anxiety disorders thus far. The predispositional model states that a
comorbid disorder precedes and increases the risk of developing AN. This model is
supported by chronology ﬁndings suggesting that anxiety disorders predate the onset of
AN in the majority Of cases.

The second model, the common cause model, asserts that common environmental
or genetic risk factors independently lead to the development of both AN and anxiety
disorders (W onderlich & Mitchell, 1997). In other words, this model posits that the
comorbidity of these disorders is due to a common underlying diathesis. Research using
twin and family study designs has begun to directly examine the common cause model by
determining whether the co-occurrence of AN and anxiety disorders is due to common
genetic or common environmental factors. However, before it can be determined
whether genes contribute to the co-aggregation of AN and anxiety disorders, it is
necessary to ascertain whether each of these disorders are heritable.

Evidence for the Heritability of AN

Accumulated evidence indicates that there is a substantial genetic component to
AN. For instance, family studies have found that ﬁrst- and second-degree relatives of
AN probands show higher rates of eating disorders compared to relatives Of normal
(Gershon et al., 1983; Strober et al., 1990; Strober et al., 2000; Lilenfeld et al., 1998) and
psychiatric controls (Strober, Morrell, Burroughs, Salkin, & Jacobs, 1985; Hudson et al.,
1983). The prevalence of AN has been found to be roughly 1 1.3 times greater in relatives

Of AN probands than relatives of controls, while the prevalence of bulimia nervosa (BN)

has been found to be 4.2 times higher than that in relatives Of controls (Strober, Freeman,
Lampert, Diamond, & Kaye, 2000). Further, relatives of AN probands have a 7 to 12
times higher rate of eating disorders not otherwise speciﬁed (EDNOS) compared to
relatives Of control women (Lilenfeld et al., 1998). Elevated rates of all forms of eating
pathology in relatives of AN probands highlight possible shared transmission of different
forms Of eating disorders (Strober et al., 2000; Lilenfeld et al., 1998). This underscores
the importance of looking at all forms of eating pathology in any examination of familial
transmission.

Taken together, ﬁndings suggest signiﬁcant familial aggregation Of AN, yet the
nature of this aggregation cannot be determined from family studies. Genetic and/or
environmental factors could potentially account for this familial clustering. However,
recent twin study ﬁndings suggest that at least some Of the aggregation is due to genetic
factors.

Twin studies of AN have found higher concordance rates in monozygotic (MZ)
relative to dizygotic (DZ) twins (Holland, Hall, Murray, Russell, & Crisp, 1984; Holland,
Sicotte, & Treasure, 1988). Since MZ twins share all of their genes, while DZ twins
share only half of their genes, higher concordance rates in MZ versus DZ twins implicate
at least a partial inﬂuence of genes on a trait/disorder. A population-based study using
the same data as the present study (Klump, Miller, Keel, McGue, & Iacono, 2001) found
that concordance rates in MZ twins ranged from 29% to 43% for narrow and broad
deﬁnitions of AN respectively, while no DZ twins were concordant for the disorder.

Heritability estimates for AN have also been consistently high. Population-based

samples have found heritabilities ranging from 58% to 74% (Wade et al., 2000;

Kortegaard, Hoerder, Joergensen, Gillberg, & Kybik, 2001; Klump et al., 2001), and
these estimates are even higher in a clinically-based sample (Holland et al., 1988).
Moreover, symptoms Of disordered eating, such as body dissatisfaction, drive for
thinness, and weight preoccupation, also show high degrees of heritability (Klump,
McGue, & Iacono, 2000; Rutherford, McGufﬁn, Katz, & Murray, 1993; Wade etal.,
1999). These genetic factors appear to exert greater inﬂuence on eating attitudes after
girls have gone through puberty (Klump et al., 2000; Klump, McGue, & Iacono, 2003).

In sum, considerable support exists for the inﬂuence Of genetic factors on the
development Of AN once girls have passed through puberty. The abundance of research
implicating the inﬂuence of genes in the development of AN suggests that part of the
comorbidity between AN and anxiety disorders may be due to shared genetic factors.
Evidence for the Heritability of Anxiety Disorders

Research on anxiety disorders reveals a similar pattern of genetic inﬂuence.
Children of parents with anxiety disorders are more likely to develop an anxiety disorder
themselves than children of parents without an anxiety disorder (Beidel & Turner, 1997;
Capps, Sigrnan, Sena, & Henker, 1996; Turner, Beidel, & Costello, 1987; Weissman,
Leckman, Merikangas, Gammon, & Prusoff, 1984). Again, although this provides
evidence for familial transmission, it is unclear from family studies whether this is due to
genetic or environmental factors.

Twin studies, however, indicate that genetic factors account for some Of the
variance in anxiety disorders. The few twin studies that have been conducted have found
higher concordance rates in MZ relative to DZ twins (Kendlcr, Neale, Kesslre, Heath, &

Eaves, 1992; Torgersen, 1983). A recent meta-analytic review Of the genetic

epidemiology of anxiety disorders yielded heritabilities of 43% for panic disorder and
32% for generalized anxiety disorder (GAD), and concluded that familial aggregation for
both of these disorders as well as the phobias is largely due to genes (Hettema, Neale, &
Kendlcr, 2001 ). It is important to note that when a range of anxiety disorders are
examined in twin studies, MZ twins tend not to be concordant for the same anxiety
disorder (Torgersen, 1983; Andrews, Stewart, Allen, & Henderson, 1990). This suggests
that transmission of anxiety disorders is non—speciﬁc, such that the genetic vulnerability
may predispose individuals to a range of anxiety-related pathologies rather than a speciﬁc
disorder per se.
Transmission of AN and Anxiety Disorders

Since both AN and anxiety disorders demonstrate evidence of genetic
transmission, and they co-occur with a high ﬁ'equency, it is possible that they share an
underlying genetic diathesis. Very few studies have examined the cross-transmission of
AN and anxiety disorders. This cross-transmission can be examined in two ways. First,
twin studies can be used to quantify the relative inﬂuence of common genetic and
common environmental factors on the co-occurrence of two disorders, such as AN and
anxiety disorders. Although this method provides the strongest evidence for cross-
transmission, the large sample sizes needed for adequate statistical power are difﬁcult to
achieve.

The second method for examining cross-transmission is the family study, where
the rates of a co-occurring disorder (i.e., an anxiety disorder) are examined in the

relatives Of an individual diagnosed with the primary disorder under study (i.e., AN). If

there are increased rates of both the cO-occurring and primary disorder in the relatives,
then there appears to be cross-transmission Of the two disorders.

There are two important features which strengthen the conclusions that may be
drawn from such a study. Firstly, it is important to stratify relatives based upon the
proband’s comorbidity status, and then compare rates Of the comorbid disorder between
relatives of probands with the comorbid disorder and relatives of probands without the
comorbid disorder. This enables researchers to ascertain whether proband comorbidity
accounts for the increased rates of the comorbid disorder in the relatives. In such a case,
the rates of the comorbid disorder would only be elevated in the relatives of probands
with a personal history of the comorbid disorder, and transmission of the primary and
comorbid disorder would thus be independent. Equally elevated rates of the comorbid
disorder in relatives, regardless Of the comorbidity status of the proband, suggest shared
transmission.

The second important feature that should be included in family studies of shared
transmission is the use Of a comparison control group consisting Of relatives of probands
with the comorbid disorder. They would be examined to determine if they showed
elevated rates of the primary disorder. This allows for the substantiation of any
suggested shared transmission.

In general, family studies have suggested that there is shared transmission
between eating and anxiety disorders. For example, a study in which a single anxiety
disorder (i.e., OCD) was examined in the relatives of probands with AN indicated that
risk for anxiety disorders was signiﬁcantly higher in AN proband relatives than in

relatives of controls (Bellodi, Cavallini, Bertelli, & Chiapparino, 2001). Likewise,

another family study examining a wide range of anxiety disorders in relatives of AN
probands found increased rates of Obsessive-compulsive disorder, generalized anxiety
disorder, panic disorder, and social phobia compared to relatives Of control women
(Lilenfeld et al., 1998). Risk for these disorders ranged from 2 to 5 times higher in
relatives of AN probands than relatives of controls. However, when the probands were
stratiﬁed by the presence or absence of the comorbid disorder, evidence of shared
transmission was only cautiously suggested for social phobia (Lilenfeld et al., 1998). In
other words, there is some evidence that AN and social phobia may share a common
familial transmissible factor, which increases risk for both disorders.

There are a number Of possible reasons that may explain why shared transmission
was not found with the other anxiety disorders. One is the small sample size. This study
had a sample size that, once stratiﬁed, may not have been large enough to detect cross
transmission between AN and other anxiety disorders. Even the potential relationship
between AN and social phobia could not be clariﬁed because of the small sample size
following stratiﬁcation. Another potential explanation for the lack of shared transmission
relates to the previously mentioned research suggesting that anxiety disorders do not
breed true (Turner et al., 1987; Torgersen, 1983). In other words, transmission does not
necessarily involve a speciﬁc anxiety disorder (i.e., social phobia is transmitted ﬁom
father to daughter), but rather a non-speciﬁc vulnerability for anxiety disorders in general
(i.e., anxiety proneness is transmitted that might translate into a social phobia, panic
disorder, etc.). Consequently, stratifying by the presence of any anxiety disorder may

have been better able to clarify relationships between AN and anxiety disorders.

10

A recent twin study has provided some of the strongest evidence of cross-
transmission of eating and anxiety disorders by using a discordant MZ twin (i.e., one twin
has the disorder, her co-twin does not) design to directly examine shared risk for these
disorders (Keel et al., in preparation). The discordant twin method involves assessing the
non-disordered cO-twins of twins with a speciﬁc disorder for the presence of a comorbid
disorder. Since MZ twins share all of their genes, if the co-twins of disordered twins
have a higher incidence of the comorbid disorder compared with the co-twins Of controls
it can be concluded that transmission is shared between the two disorders.

In this study, the cO-twins of ED twins were two times more likely to suffer ﬁom
childhood anxiety disorders compared to non-eating disordered controls. Further, there
were no differences in the rate of anxiety disorders between ED twins with or without a
childhood anxiety disorder, suggesting possible shared transmission between the two. A
strength of this study was its inclusion of a comparison group Of anxiety disordered twins
without eating pathology. Results showed that the non-disordered co-twins of the anxiety
disorder twins were more likely to be diagnosed with an ED compared to controls.
Although this study provides support for shared transmission of eating and anxiety
disorders, its results cannot be generalized to all anxiety disorders since only childhood
anxiety disorders were examined.

Only one other study has looked at the presence of anxiety disorders in the
relatives of eating disorder (ED) probands, using the relatives of probands with an
anxiety disorder (OCD) as a comparison group (Pasquale, Sciuto, Cocchi, Ronchi, &
Bellodi, 1994). The eating disorder probands were included in analyses if they were

diagnosed with AN, BN or both. In this study, familial risk for EDS was not signiﬁcantly

11

different between relatives Of OCD probands and relatives of ED probands. This lack of
familial speciﬁcity indicates partial support for a common predisposition, or Shared
transmission, as relatives of ED and OCD probands were equally likely to exhibit a
lifetime history of eating pathology. Moreover, rates of speciﬁc anxiety disorders (i.e.,
panic disorder with or without agoraphobia, GAD, and anxiety NOS) were similar across
relatives of probands with both disorders as well, although rates of OCD were
signiﬁcantly higher in relatives of OCD probands than relatives of ED probands.

The design utilized in Pasquale et al. (1994) - including a comparison anxiety
disorder group - maximizes the ability to draw conclusions about shared transmission,
however there are a few limitations that constrain the strength of the results. First, the
fact that shared transmission was not found for OCD could be related to the idea that
OCD may belong to another class of psychiatric disorders rather than to anxiety
disorders. Some controversy exists regarding the categorization of OCD as an anxiety
disorder because it shows a strong association and overlap with other, non-anxiety
psychiatric disorders (e. g., mood disorders, personality disorders, impulse control
disorders) (Brown, 1998; Hudson & Pope, 1990). Accordingly, OCD may not be
representative of all anxiety disorders and thus may not exhibit the same pattern of shared
transmission as other anxiety disorders previously investigated. This hypothesis is
corroborated by ﬁndings described above (Lilenfeld et al., 1998) that also showed a lack
of shared transmission between OCD and AN, but found evidence Of shared transmission
between AN and social phobia.

Another problem with the Pasquale et al. (1994) study is that there was no control

group with which to compare the rates of disorders found in the relatives of probands

12

with OCD or ED, SO it is not possible to say if these rates were truly elevated above those
found in the general population. A comparison group consisting of the relatives Of
probands with no eating or anxiety pathology would help to clarify whether there truly
exists a common diathesis which increases risk for both AN and anxiety disorders.
Finally, researchers did not control for proband comorbidity, which makes it difﬁcult to
clarify the nature of any transmission. As noted above, without stratiﬁcation based upon
proband comorbidity, it is difﬁcult to determine whether the elevated rates of the
comorbid disorder are simply due to the comorbidity status of the proband or due to a
shared diathesis.

TO summarize, ﬁndings suggest that there is shared transmission Of AN with
social phobia and childhood anxiety disorders. The existence of such a relationship with
other anxiety disorders remains unclear. Family studies alone cannot determine whether
genetic inﬂuences underlie the co-occurrence of these disorders, but ﬁndings from twin
studies suggest that transmission both within and between AN and anxiety disorders
appears to be at least partially mediated by genes. If this transmission is shared, as recent
research ﬁndings suggest (Keel et al., in preparation), a common genetic vulnerability
may be involved in the development of both AN and anxiety disorders. Results Of recent
twin research does indicate shared genetic transmission between BN and certain anxiety
disorders (Kendler et al., 1995), suggesting that the same may be true for AN.
Understanding possible genetic links between AN and anxiety disorders would provide
some insight into the presently elusive etiology Of AN and may aid in the prevention and

treatment of the disorder.

13

Study Objectives
Overall Purpose

The present study sought to corroborate and extend previous ﬁndings on
comorbidity and possible shared transmission by examining diagnoses in parents of
probands with AN and anxiety disorders. Speciﬁcally, this study compared the
frequencies of anxiety disorder and eating disorder diagnoses in the parents Of probands
diagnosed with either AN, an anxiety disorder, or with no eating or anxiety pathology.
The use of parental diagnoses and a comparison anxiety disorder group allowed for the
direct examination of the comorbidity models. As mentioned above, the co-occurrence of
AN and anxiety disorders may be explained by a predispositional model or a common
cause model (W onderlich & Mitchell, 1997). In the predispositional model, it is expected
that relatives of probands with AN will not show elevated rates Of anxiety disorders
unless the proband herself is also diagnosed with that disorder. In this case, anxiety
likely serves as a risk factor, simply increasing the likelihood that AN will develop.

By contrast, the common cause model posits an Opposing hypothesis, such that
the prevalence of AN and anxiety disorders would be elevated in the relatives Of
individuals with AN and relatives Of individuals with an anxiety disorder, regardless Of
whether the proband is comorbid for both disorders. This would suggest that the
disorders share a common diathesis. The present study directly examined these
hypotheses by comparing rates of eating and anxiety disorders between parents Of
probands with AN and parents of probands with anxiety disorders. Parents of AN

probands were also stratiﬁed by the presence Of an anxiety disorder in the AN probands.

14

Speciﬁc Aims and Hypotheses

The ﬁrst speciﬁc aim of the proposed study was to examine comorbidity between
AN and childhood and adult anxiety disorders. This was done by comparing rates of
lifetime anxiety disorder diagnoses between probands with AN and control probands who
comprised the remainder of the sample with no eating pathology. To increase statistical
power, these groups were also compared on a continuous measure Of anxiety pathology,
namely the State-Trait Anxiety Inventory (Spielberger, Gonsuch, & Luschene, 1970). It
was expected that probands with AN would exhibit higher rates of anxiety disorders and
symptoms than control probands.

The second speciﬁc aim was to examine possible shared transmission between
AN and anxiety disorders. Rates of anxiety disorders and eating disorders were
compared in parents of AN probands, parents of probands with any childhood or adult
anxiety disorder, and parents of probands with no eating or anxiety pathology. Roughly
equivalent rates of ED and anxiety disorders between the parents Of AN twins and the
parents Of anxiety disorder twins, with both of these rates exceeding those of the parents
of controls, would suggest that there is shared transmission Of anxiety with AN.

The ﬁnal speciﬁc aim was to directly compare the predispositional and common
cause models by stratifying parents of the AN probands based upon the presence or
absence Of an anxiety disorder in the AN proband. Increased rates of anxiety disorders in
the parents of AN probands, regardless of the comorbidity status Of the proband, would
support the common cause model of comorbidity and disprove the predispositional
model. By contrast, the predispositional model would be supported if the parents of AN

probands with a comorbid anxiety disorder had signiﬁcantly increased rates Of anxiety

15

disorders compared to the parents of probands without a personal history of anxiety
disorders. Based upon the evidence supporting the involvement of genetic inﬂuences
both within and between disorders, it was expected that the common cause model would
best explain relationships between eating and anxiety disorders.

This study has a number of strengths that improve upon previous research in this
area. First, no study to date has compared familial transmission Of eating and anxiety
disorders in probands with an eating disorder versus probands with a wide range of
childhood and adult anxiety disorders. The use of this family study design allowed for
the determination of which comorbidity model best explained the relationship between
AN and anxiety disorders. Second, the sample is population-based, circumventing the
treatment-seeking bias discussed earlier. Third, all subjects (i.e., AN, anxiety disordered,
and control subjects) were ascertained from the same sample, decreasing sample
heterogeneity that can result from sampling from several populations. Fourth, all
probands fell within a relatively narrow age range, which is important since both AN and
speciﬁc anxiety disorders have well-deﬁned ages of onset. Thus, all women have had the
same amount of time to develop the disorders under study. Finally, both categorical and
continuous measures Of eating and anxiety pathology were used. Examining both
phenotypes increased our statistical power to detect signiﬁcant shared effects.

Method
Participants

The sample is composed of a cohort of female probands (n = 672) who were

followed longitudinally over two assessment periods. Data on the probands were ﬁrst

collected at an intake assessment (conducted when the probands were roughly age 17)

16

and then again at a follow-up assessment (conducted three years later at age 20). This
sample is ﬁ'om the Minnesota Twin Family Study (MT F S), which is a population-based,
longitudinal study of the development of substance use and related behaviors in same-sex
male and female twins and their parents. When only one parent could participate in the
study, data was usually collected on the mother; twins were not included when neither
parent could participate.

Minnesota state birth records were used to determine families eligible for
recruitment. These included families with live twin births, except when the following
exclusionary criteria were met: (a) the family lived farther than a day’s drive from the
University of Minnesota’s Minneapolis campus; (b) the twin pair had a physical or
mental handicap that would preclude them ﬁ'om completing the self-report and interview
assessments; or (c) the twins had been adopted. Other exclusionary criteria have been
detailed elsewhere (Iacono, Carlson, Taylor, Elkins, & McGue, 1999). These families
were then located through public databases such as telephone directories and drivers
license registrations. Overall, the MTFS has successfully located more than 90% of twin
births in the state of Minnesota in a given year.

The study was described in detail to all potential participants. Written informed
consent was then obtained from all participants who were at least 18 years of age.
Underage participants instead provided informed assent, while written informed consent
was obtained from their parents.

In analyses examining Speciﬁc aim #1 (i.e., examining comorbidity between AN
and anxiety), the AN probands and a control group composed of the remainder Of the

sample with no eating pathology was examined. In analyses for speciﬁc aim #2, to

17

examine shared transmission between eating and anxiety disorders, the 91112113 of
probands with AN, anxiety disorders, and a control group with no eating or anxiety
pathology were included. Thus, to reiterate, for the ﬁrst analysis on comorbidity, two
subject groups were examined: (1) probands with AN syndrome (I; = 36; see details
below), which included ﬁve pairs of concordant twins (i.e., both twins have the disorder);
and (2) control probands with no eating pathology (n = 287). For the second analysis
examining shared transmission, three subject groups were included: (1) parents of
probands with AN syndrome (r_r = 31 moms and 28 dads); (2) parents Of probands with
any form of anxiety disorder (11 = 109 moms and 92 dads); and (3) parents of probands
with no eating or anxiety pathology (g = 43 moms and 41 dads).

Parents included in the AN group had at least one twin with the disorder. Anxiety
disorder parents were selected for inclusion on the basis Of having at least one twin with a
lifetime diagnosis of one or more Of the following: overanxious disorder, separation
anxiety disorder, agoraphobia, agoraphobia without panic disorder, panic disorder with or
without agoraphobia, generalized anxiety disorder, speciﬁc phobia or social phobia.
Parents of twins who had an eating disorder and an anxiety disorder were included in the
AN parent group, as were parents who had one twin with an eating disorder and the other
twin with an anxiety disorder. Parents of twins with a BN or binge eating disorder (BED)
diagnosis were excluded from analyses, given that the relatives Of women with these
disorders are at increased risk of having an eating disorder themselves (Lilenfeld et al.,
1998; Strober et al., 2000).

The control group for the ﬁrst speciﬁc aim (i.e., controls with no eating

pathology) included all twins who did not meet criteria for threshold or subthreshold (one

18

symptom short) AN, BN, or BED. For this ﬁrst analysis, one twin from each eligible pair
was randomly selected for inclusion in the control group to ensure independent
Observations within groups. Control probands for the second speciﬁc aim (i.e., controls
without eating or anxiety disorders), included all twin pairs without eating or anxiety
disorder syrnptomatology. In both cases, controls were allowed to meet criteria for other
psychiatric diagnoses (e.g., depression, ADHD) in order to provide a sample that was
most representative of the population.

Measures

Eating Disorder Diagnoses and Characteristics. The Eating Disorders Structured
Clinical Interview (EDSCI) was used to assess DSM-IV eating disorder diagnoses. This
semi-structured clinical interview is based upon the eating disorders module of the
Structured Clinical Interview for DSM Axis I Disorders (SCID I; Spitzer, Williams, &
Gibbon, 1987), and was developed by MTFS researchers to assess anorexia nervosa,
bulimia nervosa, and binge eating disorder.

A revised version of the Eating Disorders Inventory (EDI; Garner, Olrnstead, &
Polivy, 1983) was used to assess self-reported eating attitudes and behaviors. This 30-
item, computer-adnrinistered Minnesota Eating Disorder Inventory (M-EDI; Klump et al.,
2000; von Ranson, Klump, Iacono, & McGue, submitted) was developed by MTF S
researchers to facilitate use with a preadolescent population, as the MTFS assesses a
younger cohort of female twins not included in these analyses. Following factor analysis
(Klump et al., 2000), four distinct subscales emerged: (1) Body Dissatisfaction, which
assesses body shape and size dissatisfaction; (2) Weight Preoccupation, which assesses

preoccupation with dieting, weight, and the pursuit of thinness; (3) Binge Eating, which

19

assesses the tendency to engage in, or think about, overeating; and (4) Compensatory
Behaviour, which assesses the tendency to use or consider using compensatory methods
of weight control (e.g., self-induced vomiting, misuse of laxatives). In addition, an M-
EDI Total Score assesses current overall eating pathology. High M-EDI scores reﬂect
greater eating pathology.

All M-EDI scales have adequate psychometric properties, with Cronbach’s alphas
ranging from .65 - .89 (Klump et al., 2000; von Ranson eta1., submitted). Item analysis
Of these subscales indicates that the factor loadings for the M-EDI are highly similar to
those of the original EDI (Klump et al., 2000). The stability across time is also similar
between the two instruments, as indicated by the M-EDI’S three-year stability coefﬁcients
of .31 to .60 (Klump et al., 2000; von Ranson et al., submitted) compared to the EDI’s
one-year correlations ranging hour .44 to .75 (Garner, 1991). In addition, the M-EDI
subSCales Show high discriminatory ability between women with eating disorders and
non-eating disordered controls (von Ranson et al., submitted).

Anxiety Disorder Diagnoses and Characteristics. The Diagnostic Interview For
Children and Adolescents — Revised (DICA-R; Reich & Welner, 1988) was used tO
assess the DSM-III-R childhood anxiety disorder diagnoses of overanxious and
separation anxiety disorder. Other DSM-III-R anxiety disorders, such as social and
speciﬁc phobias, generalized anxiety, PTSD, panic disorder with or without agoraphobia,
agoraphobia, and agoraphobia without panic disorder were assessed with the SCID I
(Spitzer et al., 1987).

The State-Trait Anxiety Inventory (Spielberger et al., 1970) was used to assess

self-reported anxiety. This 40-item scale is well-established as a measure of both

20

transitory (state) and stable (trait) levels of anxiety. Both the state and trait subscales
consist of 20 statements, with 4—pOint Likert scale responses. On the state scale,
respondents evaluate how they are feeling at that very moment, while on the trait scale,
responses are made regarding how they generally feel. Higher scores reﬂect greater
levels of state or trait anxiety. This scale has been validated on a number of different
populations, and norms are available for working adults, college and high school students
(Spielberger et al., 1970). Stability coefﬁcients are quite high for the trait scale (range =
.65 - .86), while those for the state scale are rather low (range = .16 - .62), reﬂecting its
sensitivity to situational factors which exist at the time of testing (Spielberger, 1983).
The scale correlates well with other measures of anxiety (Spielberger et al., 1970),
supporting its validity. Moreover, when individuals were assessed with the STAI prior tO
and following a stressful situation, only the state measure showed any change, supporting
the differentiating power of the STAI (Metzger, 1976). Probands were administered both
the state and trait subscales, while parents only completed the trait subscale.
Diagnostic Procedures

All of the structured interviews were administered face-tO-face by trained clinical
interviewers, with separate interviewers conducting assessments of co-twins and their
parents. A clinically trained diagnostic team then evaluated the item coding. The initial
coding Of items and the diagnostic evaluations for parents and co-twins were conducted
blind to the diagnosis of the proband. Computer algorithms based upon DSM-III-R (for
anxiety disorders) and DSM-IV (for eating disorders) criteria then generated diagnoses.

For the anxiety disorders, participants were considered to be positive for the

disorder if they met full DSM-III-R criteria. All probands who met criteria for AN

21

syndrome at intake or follow-up were included in analyses. The AN syndrome diagnostic
category includes participants who met full DSM-IV criteria for AN, were one symptom
short (note that the one symptom short could not be, by deﬁnition, low body weight), or
were subthreshold for the disorder. A subthreshold diagnosis was given when a subject
was 5 90% ideal body weight (IBW), and had a disturbed body image (intense fear of
gaining weight or becoming fat, disturbance in perception of body size or shape, or undue
inﬂuence of body Shape or weight on self-evaluation), and an M-EDI score above the
mean (11.0) Of probands who met ﬁrll criteria for anorexia nervosa.

The eating disorder criteria differed for parental data. Fathers were not assessed
for eating disorders, and only those mothers who met full DSM-IV criteria for an eating
disorder (anorexia nervosa, bulimia nervosa, or binge eating disorder) or fell one
symptom short were deemed to have a positive diagnosis. Subthreshold diagnoses could
not be given for parents, as the M-EDI assesses current eating pathology, and most
mothers who were positive for a lifetime diagnosis of eating disorder would have
experienced the disorder in the past.

Interrater reliability of assigned diagnoses was determined at intake by comparing
the diagnostic evaluations of two independent consensus teams. Non-eating disorder
diagnoses had relatively high kappa coefﬁcients: 0.77 for separation anxiety disorder;
0.92 for overanxious disorder; 0.93 for panic disorder; 0.79 for agoraphobia; 0.85 for
panic disorder with agoraphobia; 0.74 for panic disorder without agoraphobia; 0.80 for
social phobia; and 0.75 for simple phobia. Reliability information on GAD was not
available because of its low prevalence rate. The kappa coefﬁcient for AN was slightly

lower at .62. T 0 ensure the validity of AN diagnoses, two MTFS researchers reviewed

22

each case individually after its initial review, and added the criterion of minimum M-EDI
scores (as described above).
Statistical Analyses

A p_ value of .05 was used for all analyses. Statistical analyses for each speciﬁc
aim were as follows:

Speciﬁc Aim 1 : In order to examine comorbidity of eating and anxiety pathology,
frequencies of anxiety disorders were compared between the AN syndrome proband
group and the control group with no eating pathology using a chi-Square test Of
independence. Fisher’s exact test was implemented when the sample size for a particular
group was less than ten. In addition, STAI scores were compared between AN syndrome
probands and control probands using independent samples t-tests.

Specific Aim 2: The cross-transmission of anxiety and eating disorders was
examined by:

(a) comparing ﬁ'equencies of anxiety disorders, eating disorders, and ‘no eating or
anxiety diagnoses’ between the mothers and fathers of AN syndrome probands, anxiety
disorder probands, and control probands with no eating or anxiety pathology. Again, chi-
square tests were implemented to analyze the diagnostic data, using Fisher’s exact test
where appropriate. These initial analyses were followed by prediction analyses for cross-
classiﬁcations (von Eye, 1997) to test the speciﬁc hypothesis that AN and anxiety
disorder parents would have elevated frequencies of eating and anxiety disorders
compared to the control parents.

Prediction analysis is a statistical procedure which allows for the examination of

speciﬁc sets of point predictions between predictor and outcome variables. It is similar to

23

chi-square in that it examines associations between categorical variables, but it is a more
precise and powerful test because it allows one to make direct predictions regarding
associations. Prediction analysis provides an overall test of the signiﬁcance Of the model,
or how well the predictions were supported by the data, and also tests the success of
predictions for each individual variable. Negative prediction success suggests that the
predictions were less accurate than would be expected ﬁ'om chance. On the other hand,
positive prediction success indicates that there was a greater reduction in the error rate
than would be expected by chance, and therefore that the predictions made correspond to
the actual associations between predictor and outcome variables found in the data. The
speciﬁc predictions that were tested were that parents Of probands with AN or an anxiety
disorder would have increased rates of both eating and anxiety disorders, while parents Of
controls would have increased rates Of ‘nO eating or anxiety diagnoses’.

Odds ratios were also calculated to determine the likelihood of parents of AN and
anxiety probands having an eating or an anxiety disorder diagnosis compared to that of
the controls. Odds ratios allow for direct comparisons to be made between the diagnostic
groups and non-diagrrostic groups (controls), and unlike prediction analysis, Odds ratios
do not rely upon base rates.

In order to control for the possible effects of proband comorbidity, these analyses
were conducted on the entire AN syndrome group, and also with the AN group divided
into those with a comorbid anxiety disorder and those without a diagnosed anxiety
disorder. Here, the shared transmission hypothesis asserts that AN parents would Show
elevated rates Of anxiety disorders regardless Of whether the AN proband had a personal

history Of an anxiety disorder.

24

(b) comparing scores on continuous measures of eating and anxiety pathology
(M-EDI and STAI-Trait) between parents of probands with AN, anxiety disorders, and
control probands using analysis of variance (ANOVA) with follow-up Tukey’s post-hoe
t-tests.

Results
Analysis 1 : Examining Comorbidity in Proband Sample

For Analysis 1, rates of anxiety disorders were compared between probands with
AN and the remainder of the proband sample using chi-square analyses to examine
whether AN women have higher rates of anxiety disorders than a general population
sample with no eating pathology (see Table 1). The results indicate that women with AN
had higher rates of PD, PD without agoraphobia, speciﬁc phobia, GAD, and ‘any anxiety
disorder’ than control probands without any eating pathology. There was also a trend
towards higher rates of overanxious disorder and PTSD in probands with AN. NO
signiﬁcant differences in the rates of the other anxiety disorders emerged.

Anxiety pathology was further examined by comparing mean scores on the STAI
between probands with AN and the rest of the sample. T-test results, as shown in Table
2, indicate that there are no differences in scores on either the State or Trait subscales of
the STAI for women with AN versus controls with no eating pathology. An additional
analysis, shown in Table 3, was performed to determine whether a high rate of anxiety
disorders amongst controls could account for the lack of differences. However, when
women with anxiety disorders were removed from the control sample, there were still no
diﬂ‘erences in STAI scores between women with AN and controls without eating or

anxiety diagnoses.

25

Analysis 2: Examination of the cross-transmission of eating and anxiety disorders.

For Analysis 2, rates Of eating and anxiety disorders were compared in parents Of
probands with either AN, an anxiety disorder, or no eating or anxiety pathology in order
to determine whether there is shared transmission between eating and anxiety disorders.
If Shared transmission exists, rates of eating and anxiety disorders would be greater than
expected for parents of probands with either an eating or an anxiety disorder.
Frequencies of all parental eating and anxiety disorders are depicted in Table 4. Due to
low rates Of individual disorders, analyses were not performed on separate diagnoses.
Instead, all eating disorders were combined into an ‘ED’ group, and individual anxiety
diagnoses were combined into an ‘anxiety disorder’ group.

Diagnostic data for these combined groups are presented in Table 5. The chi-
square analysis examining rates of ED, anxiety disorders and ‘nO eating or anxiety
diagnoses’ between parents of probands with AN, probands with an anxiety disorder, and
control probands was signiﬁcant, suggesting that there were differences in frequencies of
eating and anxiety disorders and ‘no eating or anxiety diagnoses’ between the three
parental groups. The overall model for prediction analysis was also signiﬁcant,
indicating that parents of probands with AN and parents of probands with an anxiety
disorder had increased rates of both EDS and anxiety disorders, while parents of controls
had a greater than expected frequency of ‘no eating or anxiety diagnoses’. The reduction
in error compared to that expected randomly for each individual hypothesis was 29.0%
for parents of probands with AN, 1.1% for parents Of probands with an anxiety disorder,

and 22.1% for parents of controls. Thus, the strength of the prediction varied between the

26

groups, with the predictions most strongly supporting the results found in parents Of
women with AN and parents Of controls.

Odds ratios provide additional information regarding the prevalence Of eating and
anxiety disorders in parents Of probands with AN or an anxiety disorder, compared to
controls. Parents Of probands with AN were 9.4 times more likely to have an ED and 2.3
times more likely to have an anxiety disorder compared to controls, with both results
achieving signiﬁcance. Odds ratios for parents of anxiety disorder probands did not
reach signiﬁcance, but they suggest that parents of probands with an anxiety disorder
were more likely to have an ED, while they were not more likely to have an anxiety
disorder. Similar to the prediction analysis ﬁndings, there is stronger support for shared
transmission in parents of probands with AN. The weaker support in parents of probands
with an anxiety disorder appears to be primarily due to a lack of familial transmission Of
anxiety disorders.

Comparable results were found for continuous measures of eating and anxiety
pathology (see Table 6). Parents of probands with AN showed the highest levels of
eating and anxiety pathology, as their mean scores were signiﬁcantly higher than parents
Of controls on M-EDI Total Score, Binge Eating, and STAI-T. Parents Of probands with
AN and parents of probands with an anxiety disorder had higher mean scores on Weight
Preoccupation than parents Of control women. Together these results suggest some
shared transmission of pathology that, similar to the diagnostic ﬁndings, is more strongly
supported by parents of probands with AN. Overall, parents of probands with AN
endorsed the most pathology on all scales, followed by parents Of probands with an

anxiety disorder, whereas parents Of control probands had the lowest mean scores.

27

Proband Stratiﬁcation

As noted above, parents in the AN group were divided according to comorbidity
in the proband in order to ensure that elevated rates of eating and anxiety disorders in the
AN parental group were not due to the presence of a comorbid anxiety disorder in the
proband. As well, the lack of familial aggregation of anxiety disorders was an
unexpected ﬁnding, and one possible explanation for this result was that differences in
familial aggregation may exist between families with one versus multiple anxiety
disorder diagnoses. Therefore, anxiety disorder probands were also stratiﬁed by
comorbidity and analyses were re-run on their parents. There were four resultant parent
groups that included parents of probands with: (1) AN only; (2) AN and a comorbid
anxiety disorder; (3) a single anxiety disorder; and (4) more than one anxiety disorder.
Rates of EDS and anxiety disorders in these parents were then examined along with
parents of controls (see Table 7). The chi-square indicates that there is a signiﬁcant
difference in frequencies of eating and anxiety disorders between parent groups.

The prediction analysis was also signiﬁcant. This suggests that in general, parents
Of probands with AN or anxiety disorders had increased rates of both EDS and anxiety
disorders, while parents of controls had a higher than expected frequency of individuals
without an ED or an anxiety disorder. When examining the individual hypotheses,
prediction error was reduced by 20.4% for parents of probands with AN only, 35.0% for
parents of probands with AN and an anxiety disorder, and 33.5% for parents of probands
with more than one anxiety disorder. However, there was negative prediction success for

parents Of probands with only one anxiety disorder, suggesting that the lack of shared

28

transmission previously found in parents of probands with an anxiety disorder was due to
low rates for transmission of eating and anxiety disorders within this group.

These results are supported by Odds ratio ﬁndings. They indicate that parents Of
probands comorbid for AN and an anxiety disorder were more likely to have an eating
disorder or an anxiety disorder than parents of controls. Although these same analyses
did not reach signiﬁcance with parents of probands with AN only, the magnitude of the
Odds ratios suggest increased rates of both disorders. Parents of probands with two or
more anxiety disorders also have increased rates of eating disorders and a trend towards
higher rates of anxiety disorders compared to controls. Finally, parents of probands with
only one anxiety disorder were not signiﬁcantly more likely to have an eating disorder or
an anxiety disorder.

Continuous M-EDI and STAI-T data on the stratiﬁed AN and anxiety sample is
presented in Table 8. A review of the means for the M-EDI indicates that parents Of
probands with AN only, AN and a comorbid anxiety disorder, or multiple anxiety
disorders had similarly high scores on Total Score and Weight Preoccupation. However,
small sample sizes may have limited the ability to detect signiﬁcant effects, as differences
are only indicated between parents of probands with multiple anxiety disorders and
parents of controls on these scales. On Binge Eating and Trait Anxiety, parents of
probands with multiple anxiety disorders and parents of probands with both AN and an
anxiety disorder had signiﬁcantly higher mean scores than parents of controls. In
general, these results concur with the diagnostic ﬁndings suggesting that the strongest
rates Of cross-transmission are found in parents of women comorbid for AN and an

anxiety disorder or with multiple anxiety disorders. However, higher M-EDI scores,

29

although not signiﬁcantly different from controls, also suggest increased transmission of
eating pathology in parents of probands with AN only.
Discussion

The present study conﬁrms past ﬁndings of high frequencies of anxiety disorders
in women with AN. Moreover, the present ﬁndings also contribute to the scant literature
on shared transmission between eating and anxiety disorders. Support for cross-
transmission was indicated, as parents of probands with AN showed elevated rates Of
both eating and anxiety disorders which could not be entirely accounted for by proband
comorbidity. Cross-transmission was also conﬁrmed in parents of probands with an
anxiety disorder when considering multiple anxiety diagnoses. Thus, cross-transmission
Of eating and anxiety disorders was apparent in both the AN and the anxiety disorder
samples. These ﬁndings also attest to the importance of including a control anxiety
disorder group, as different rates of transmission were noted between in the AN proband
group and the anxiety proband group. The anxiety disorder comparison group provided
important insight into factors which may inﬂuence transmission rates, such as
comorbidity of anxiety disorders in both AN and anxiety disorder families.
Comorbidity of Eating and Anxiety Disorders in Probands

The present study corroborated previous ﬁndings Of increased rates of anxiety
disorders in individuals meeting criteria for AN syndrome. Nearly 50% of AN
individuals in this sample met full criteria for a lifetime anxiety disorder. This rate is
somewhat lower than those previously found in studies examining lifetime rates of both
childhood and adult anxiety disorders in a treatment-seeking sample (Bulik et al., 1997;

Godart et al., 2000). However, the present rates are considerably higher than those

30

Obtained by researchers who only focused on adult anxiety disorders in population-based
samples (Walters & Kendlcr, 1995) or treatment-seeking samples Of AN patients (Braun
et al., 1994; Fornari et al., 1992; Herzog et a1, 1992). Thus, the combined use Of a
population sample, along with the inclusion Of both childhood and adult anxiety
disorders, may have provided a more accurate representation of rates Of anxiety disorders
for women with AN in the general population.

It is difﬁcult to interpret the comparisons between women with AN and controls
with no eating pathology for the individual anxiety disorders since many did not reach
signiﬁcance. The ﬁ'equencies of most of the adult anxiety disorders are quite low, partly
due to the young ages of the participants, which reduced the ability to detect statistically
signiﬁcant effects. Most previous studies of comorbidity included women who were at
least approximately ﬁve years older than the present sample (Braun et al., 1994; Bulik et
al., 1997; Deep et al., 1995; Halrrri et al., 1991; Lilenfeld et al., 1998; Toner et al., 1988).

The only published study that used a community-based sample to examine
anorexia and anorexic-like syndromes found increased rates of all Of the anxiety disorders
assessed within that study (GAD, PD, and phobias (undifferentiated)), although these
rates differed between ED diagnostic spectrums (Walters & Kendlcr, 1995). The present
study has produced an exact replication Of those results, as higher rates of GAD, PD, and
speciﬁc phobia were found in women with AN compared to controls. Moreover, the
present study extended upon this previous community investigation by ﬁnding trends
towards women with AN having increased rates of both overanxious disorder and PTSD.

Considering that women with AN had increased rates of anxiety disorders, it was

somewhat unexpected that this ﬁnding did not extend to the continuous anxiety pathology

31

data. Neither state nor trait anxiety scores were signiﬁcantly different between women
with AN and control women with no eating pathology, even after removing control
individuals who met criteria for an anxiety disorder. A previous study using the STAI
found differences in scores between healthy controls and women with AN (Pollice, Kaye,
Greeno, & Weltzin, 1997). It should be noted that the control women employed in this
previous study were meticulously screened to ensure that they had no comorbid Axis I
disorders, while the present control sample was only screened for eating and anxiety
pathology. The use Of completely clean controls maximizes the chances of Observing
differences across groups and increases the chances for signiﬁcant effects when
compared to analyses of unscreened controls.

Thus, in general, the present ﬁndings replicate previous results by conﬁrming
high frequencies of anxiety disorders in individuals with AN. The use of a population-
based sample, along with the inclusion of both childhood and adult anxiety disorders,
increases generalizability and provides more accurate estimates of comorbidity than those
derived from purely clinically-based samples.

Cross-transmission of eating and anxiety disorders

The ﬁndings of the present study lend initial support to the possibility that there is
cross-transmission of eating and anxiety disorders. Women with AN are more likely than
controls to have parents with either AN or an anxiety disorder. After separating AN
parents based upon the presence or absence of a comorbid anxiety disorder in their
daughters, transmission rates are stronger in parents of women with both AN and an
anxiety disorder; however there are trends suggesting that increased rates of eating and

anxiety disorders also exist in parents of probands with AN only. It thus appears as

32

though the cross-transmission evident in parents of probands with AN cannot be
accounted for solely by proband comorbidity.

In order to conﬁrm cross-transmission, there must also be elevated rates of eating
and anxiety disorders in the parents of probands with an anxiety disorder. Initially, this
support was not found, as parents of probands with anxiety showed only a slightly
increased rate of eating disorders, but not anxiety disorders. Levels of trait anxiety also
were not elevated in parents of women with an anxiety disorder. However, when
probands were divided into parents of probands with a single anxiety disorder versus
those with multiple anxiety disorders, anxiety comorbidity in the proband was associated
with increased eating and anxiety pathology in parents. Thus, the cross-transmission
found in parents of probands with AN was conﬁrmed in the anxiety disorder group when
only the parents of probands with multiple anxiety disorders were considered.

These results attest to the importance of including a control anxiety group in any
study Of shared transrrrission between eating and anxiety disorders, as results from the ED
group alone may provide an incomplete depiction of shared transmission between eating
and anxiety disorders. Shared transmission cannot be fully supported unless it is
conﬁrmed in both the relatives of individuals with ED and those with anxiety disorders.
Additional features of transmission, such as the inﬂuence of anxiety comorbidity, may
only become apparent when such a comprehensive design is employed.

The lack of transmission of anxiety associated with single anxiety disorders was
unexpected, as the familial transmission of anxiety disorders (Beidel et al., 1997;
Hettema et al., 2001; Mancini, van Ameringen, Szatrnari, Fugere, & Boyle, 1996) and

anxiety pathology (Andrews et al., 1990; Stein, J ang, & Livesley, 1999) has received

33

considerable support. Having a relative with an anxiety disorder may increase one’s risk
Of developing a different anxiety disorder (Andrews et al., 1990; Torgersen, 1983), and
this lack of speciﬁcity in transmission was controlled for by examining all anxiety
disorders in the parents of probands meeting criteria for any anxiety disorder. In spite Of
this, there was still no evidence of transmission in parents whose daughters were
diagnosed with a single anxiety disorder.

Certain anxiety disorders may exhibit a greater genetic inﬂuence than others
(Torgersen, 1983), and heritabilities for anxiety disorders only fall in the modest range
(Hettema et al., 2001), which may have contributed to the lack of independent
transmission. However, the ﬁnding that increased rates of transmission are associated
with comorbidity raises the possibility that previous studies that examined clinical
populations may have included many probands with multiple anxiety disorders.
Treatment-seeking has been associated with increased comorbidity (Galbaud et al.,
1993), and the use of clinical samples may have therefore resulted in increased anxiety
disorder comorbidity and thus support for the familial aggregation of these disorders.

There are some potential explanations for the ﬁnding that transmission is
associated with multiple, but not single, anxiety disorders. Anxiety disorders are the
most common psychiatric disorders diagnosed in the general population (Pollack et al,
2002), so it is not particularly unusual to meet criteria for a single anxiety disorder during
one’s lifetime. However, meeting criteria for more than one anxiety disorder may
represent a shift from a relatively normative diagnosis to a more severe condition.
Certain inﬂuencing factors may be required to pass this threshold; perhaps genetic factors

are involved in the development of a broad range Of anxiety symptoms which are then

34

exhibited through comorbidity of anxiety disorders. Further, this increased heritability
may account for the higher rates of eating disorders and general eating pathology in
parents Of probands with comorbid anxiety diagnoses as shared genetic factors may
underlie the relationship between eating and anxiety disorders. Future studies Of the
transmission of anxiety disorders should examine familial aggregation and heritability for
single versus multiple anxiety diagnoses to determine whether comorbidity does
represent a greater genetic inﬂuence.

Another possibility is that higher levels of pathology in general lead to more
pathology within families. Results here indicate that women who met criteria for more
than one disorder, whether it was multiple anxiety diagnoses or AN and an anxiety
diagnosis, were more likely to have parents exhibiting some form of pathology. Given
that shared transmission Of anxiety and mood disorders has also received support (Turner
et al., 1987), attempts should be made to decipher whether there is true speciﬁcity in the
transmission of eating pathology and anxiety disorders, or if high levels of pathology
simply produce a non-speciﬁc vulnerability for a broad spectrum of psychiatric disorders.
Models of Comorbidity

One of the original Objectives of the present study was to determine which model
of comorbidity could best account for the relationship between eating and anxiety
disorders. TO recap, the two explanatory models for comorbidity Of eating and anxiety
disorders that were introduced earlier were the common cause model and the
predispositional model. The common cause model purports that eating and anxiety
disorders are independent disorders which share a common underlying diathesis, while

the predispositional model asserts that high rates of comorbidity between eating and

35

anxiety disorders are due to increased risk for AN following the prernorbid onset of an
anxiety disorder (W onderlich & Mitchell, 1997).

The results of the present study cannot be used to discount the predispositional
model, as the results of the proband stratiﬁcation were somewhat ambiguous. While the
prediction analysis supported increased rates of eating and anxiety disorders in parents Of
probands with AN only, the odds ratios were not as deﬁnitive due to small sample sizes
and the resultant broad conﬁdence intervals. However, the odds ratios were of a large
magnitude, so despite being imprecise estimates they suggest that parents of probands
with AN only do have increased rates of eating and anxiety disorders. This conclusion is
in line with the common cause model. Therefore, the trends towards increased rates of
eating and anxiety disorders in parents of probands with AN despite proband comorbidity
provide support for the common cause model, yet do not rule out the predispositional
model as a explanation for comorbidity between eating and anxiety disorders. Additional
family and longitudinal research is required in order to clarify the comorbidity model
which can best account for the relationship between ED and anxiety disorders.
Conclusions and Study Limitations

In conclusion, these ﬁndings provide support for shared transmission of eating
and anxiety disorders. Previous studies have used different designs to examine shared
transmission, which has resulted in somewhat different conclusions (Keel et al., in
preparation; Lilenfeld et al., 1998; Pasquale et al., 1994). The present study improved
upon those conducted previously by combining anxiety disorders into a single entity,
using a comparison anxiety disorder proband group as well as a control group without

eating or anxiety pathology, and stratifying the proband group for the presence or absence

36

Of a comorbid anxiety disorder. Despite the increased stringency of this design, some
questions remain abOut the nature of the relationship between eating and anxiety
disorders, and follow-up is required to further investigate shared transmission. All Of
these procedures, however, should be maintained in the future in order to provide
consistency across studies so that stronger conclusions may be drawn regarding shared
transmission.

Nonetheless, a number Of limitations of the present study should be noted. First
and foremost is the small sample size. AN is a relatively rare psychiatric disorder. A
number Of analyses approached but did not reach signiﬁcance, and the small sample Size
may have contributed to the inability to detect signiﬁcant effects. This study should be
replicated with larger AN and control samples to replicate and clarify the present
ﬁndings.

Another limitation is that some potentially important diagnostic information was
not collected for this study. Speciﬁcally, OCD was not assessed. There appears to be a
strong relationship between AN and OCD, as there are high rates of comorbidity in
women with AN (Godart, Flament, Perdereau, & J earnmet, 2001) as well as women with
OCD (F ahy, Osacar, & Marks, 1993), and ﬁrst-degree family members of women with
AN have increased rates Of OCD (Lilenfeld et al., 1998). The single study in which
proband stratiﬁcation was used to examine the relationship between AN and OCD found
that the increased rates of OCD in relatives Of women with AN were due to proband
comorbidity and not cross-transmission (Lilenfeld, 1998). However, this result has yet to

be replicated, and the nature of the relationship between AN and OCD remains unclear.

37

In addition, no diagnostic information was collected on eating disorders (ED) in
fathers. Although ED are quite rare in males, fathers of AN probands evidenced high
levels of eating pathology on the M-EDI (data not shown). Eating disorder diagnostic
information would have therefore supplemented these continuous data and increased
sample sizes for the odds ratios, which may have lead to more deﬁnitive support for
shared transmission. Finally, ﬁrst degree relatives other than parents were not included.
Although another study found similar results using the co-twins of the probands in the
present sample (Keel et al., in preparation), additional information ﬁ'om other ﬁrst-degree
relatives, such as non-twin siblings, would provide a more thorough analysis of cross-
transmission.

As a ﬁnal note, due to their young ages, many Of the participants have not yet
passed through the periods of risk for eating disorders or adult anxiety disorders. Women
in the anxiety disorder group may go on to develop an eating disorder, and some women
in the eating disorder group may develop an anxiety disorder at some point in their
lifetime. Consequently, it is possible that the data on both comorbidity and transmission
may change over time, as crossover may occur between proband groups. Nonetheless,
probands included in this study have nearly passed through the peak periods Of risk for
the development of both AN and most of the anxiety disorders (American Psychiatric
Association, 1994). It is not unusual for the onset of some anxiety disorders, such as
panic disorder, GAD, and PTSD, to occur much later in life, but it would be prohibitive
to wait out such long risk periods prior to assessment Of shared transmission. Moreover,
participants in the present study were not a great deal younger than individuals included

in other studies of comorbidity and transmission of eating and anxiety disorders (Braun et

38

al., 1994; Bulik et al., 1997; Deep et al., 1995; Halmi et al., 1991; Lilenfeld et al., 1998;
Toner et al., 1988). Therefore, despite the young ages of probands, these results provide
important initial data regarding comorbidity and transmission between disorders, and as

such are important for understanding the development Of eating and anxiety disorders.

39

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45

Table 1.

Appendix

Lifetime rlates of anxiety disorders among probands with anorexia nervosa and control

 

probands without eating pathology.

 

 

Diagnosis in Probands AN Control 13 p
(g = 36) (n = 287)

Any anxiety disorder 17 (47.22%) 79 (27.53%) 5.94 0.02
Panic Disorder 2 (5.56%) 0 16.61 0.01
Agoraphobia 1 (2.78%) 0 8.56 0.11
Panic Disorder with Agoraphobia 0 0 --- ---

Panic Disorder without Agoraphobia 2 (5.56%) 0 6.61 0.01
Agoraphobia without Panic Disorder 0 1 (0.35%) .118 0.90
Speciﬁc Phobia 8 (22.22%) 32 (11.15%) 4.14 0.04
Social Phobia 5 (13.89%) 34 (11.85%) .145 0.70
Generalized Anxiety Disorder 3 (8.33%) 2 (0.70%) 13.25 0.01
Post-Traumatic Stress Disorder 2 (5.56%) 3 (1.05%) 4.78 0.09
Separation Anxiety Disorder 2 (5.56%) 17 (5.92%) .037 0.85
Overanxious Disorder 7 (19.44%) 24 (8.36%) 3.84 0.05

 

46

Table 2.

T-test comparing mean scoraa on State Trait Anxiegr Inventory (STAI) subscales
between probands with aporexia nervosa (AN) or no eating pathology (Controls).

 

 

 

 

 

STAI Subscale AN Controls t p
(p = 35) (p = 278-279)

State 34.02 (8.71) 34.50 (8.00) 0.34 (312) .74

Trait 37.83 (7.65) 37.74 (8.21) -0.06 (311) .95

 

 

47

Table 3

T-test comparing mean scores on State Trait Anxiety Inventory (STAI) subscaﬁs
between probands with anorexiaLnervosa (AN), probands with anxiety, and probands with
no eating or anxiety diagposes (Controls).

 

STAI A B C E (df) p Contrast

Subscale AN Anxiety Controls Results
(p = 35) (p = 78—79) (p = 200)

State 34.02 (8.71) 37.41 (7.85) 33.36 (7.78) 7.49 (2) .001 B > C

Trait 3783065) 41.20 (8.55) 36.00 (7.41) 18.03 (2) <.001 B>A,C

 

48

 

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49

Table 5.

Comparison of rates of eating disorders (ED), anxiety disorders._a_rnd no eatin or anxie
pathology among parents of probands with anorexia nervc§a (AN). an anxieg disorder,
or no eating or anxieg pathology (Controls).

 

 

 

 

 

Diagnosis in Parents Parents of AN Parents of Parents of
(r_1 = 59) Anxiety Controls
(Q = 201) (Q = 85)
ED 5 (8.47%) 9 (4.48%) 0
Anxiety Disorder 28 (47.46%) 69 (34.33%) 24 (28.24%)
No eating or anxiety diagnoses 14 (23.73%) 60 (29.85%) 31 (36.47%)

Model Stﬁatistics

Chi Square 13: 9.87; df = 4; p = .04
Prediction Analysis ; = 1.76; p = .04

Odds Ratios

Parents of probands with AN OREDa = 9.38 (1.10 — 80.05)*

ORA... = 2.30 (1.14 — 4.60)*
Parents of probands with anxiety OREDa = 4.46 (0.56 — 35.36)

011m: 1.33 (0.76 — 2.31)

 

Note. All odds ratios compared rates of disorders in the diagnostic group to those in the
control group. 95% conﬁdence intervals for the odds ratios are noted in parentheses.
aThis odds ratio was calculated by adding 1 to each cell in order correct for cell values of
0.

* p<.05

50

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