Personality disorders and time to remission in generalized anxiety disorder, social phobia, and panic disorder

BACKGROUND: This investigation assessed the effect of personality disorders (PersDs) on time to remission in patients with generalized anxiety disorder, social phobia, or panic disorder. METHODS: Selected Axis I and II predictors of time to remission during 5 years of follow-up were assessed in 514 patients with 1 or more of these anxiety disorders who participated in the Harvard/Brown Anxiety Research Program, a multisite, prospective, longitudinal, naturalistic study. RESULTS: The presence of a PersD predicted a 30% lower likelihood of generalized anxiety disorder remission, a 39% lower likelihood of social phobia remission, and no difference in likelihood of panic disorder remission. More specifically, a lower likelihood of remission from generalized anxiety disorder was predicted by the presence of avoidant PersD (34% lower) and dependent PersD (14% lower). The presence of avoidant PersD predicted a 41% lower likelihood of social phobia remission. The presence of major depressive disorder did not account for these findings. CONCLUSIONS: Our findings provide new data on the pernicious effect of PersDs on the course of generalized anxiety disorder and social phobia but not panic disorder, suggesting that PersDs have a differential effect on the outcome of anxiety disorders.     

History of childhood abuse in panic disorder,social phobia,and generalized anxiety disorder

The authors examined the prevalence of self-reported childhood physical or sexual abuse in a sample of adult patients presenting for treatment of panic disorder, social phobia, or generalized anxiety disorder. Regardless of the presence of comorbid anxiety disorders or comorbid depression, patients with panic disorder had significantly higher rates of past childhood physical or sexual abuse than patients with social phobia. Patients with generalized anxiety disorder had intermediate rates of past physical or sexual abuse that were not significantly different from the other two diagnostic groups. Anxiety disorder patients with a history of childhood abuse were also more likely to have comorbid major depression than those without. These findings are discussed in terms of biological and behavioral factors that may influence the development of anxiety disorders after the experience of a traumatic event.     

Characteristics and course of panic disorder and panic disorder with agoraphobia in primary care patients

Objective: To examine the course of panic disorder (PD) and panic disorder with agoraphobia (PDA) in 235 primary care patients during a 3-year period.Method: Patients were recruited from primary care waiting rooms and diagnosed using the Structured Clinical Interview for DSM-IV. They were reassessed at 6 months, 1 year, and annually thereafter for diagnosis, treatment, and other clinical and demographic variables. Recruitment occurred between July 1997 and May 2001.Results: At intake, 85 patients were diagnosed with PD and 150 were diagnosed with PDA. Patients with PD were significantly more likely to achieve recovery (probability estimate, 0.75) from their disorder than patients with PDA (0.22) at the end of 3-year follow-up (p < .0001). There was no difference in recurrence rates between the 2 disorders. Women were more likely to recover from PD (p = .001). At intake, comorbid generalized anxiety disorder (p = .004), higher Global Assessment of Functioning score (p = .0003), and older age at panic onset (p = .05) were related to recovery from PDA, and comorbid major depressive disorder (p = .05) and psychosocial treatment (p = .002) predicted remaining in an episode of PDA. The relationship between psychosocial treatment and poor recovery must be interpreted with caution and is most likely due to the treatment bias effect.Conclusion: Primary care patients with PDA have a chronic course of illness, whereas those with PD have a more relapsing course. Given the significant burden of PD and PDA in primary care, attention to factors relevant to the course of these disorders is important for recognition and for continued improvement of treatment interventions in this setting.     

Impact of comorbid anxiety disorders on outcome in a cohort of patients with bipolar disorder

BACKGROUND: High rates of comorbid anxiety disorders have been described in individuals with bipolar disorder. Although it is well recognized that anxiety disorders often co-occur with bipolar disorder, few studies have examined the impact of more than 1 anxiety disorder on long-term outcome in patients with bipolar disorder. METHOD: The rates of DSM-IV generalized anxiety disorder, panic disorder, social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder were determined using structured clinical interviews in 138 patients with bipolar disorder who presented consecutively between 1994 and 1999. Patients were then followed for up to 3 years with longitudinal clinical surveillance. The impact of 1 or more comorbid anxiety disorders on mood symptoms and general function was evaluated. RESULTS: In our sample, 55.8% of the patients had at least 1 comorbid anxiety disorder, and 31.8% had 2 or more anxiety disorder diagnoses. The most common anxiety disorder was generalized anxiety disorder, followed by panic disorder. The presence of an anxiety disorder led to significantly (p <.05) worse outcome on global as well as specific illness measures, including illness severity, proportion of patients characterized as euthymic, and proportion of the year spent ill. Number of anxiety disorders was less important than type, with generalized anxiety disorder and social phobia having the most negative impact on outcome. CONCLUSION: Our data suggested that multiple anxiety disorder comorbidities were not infrequent in bipolar disorder and that generalized anxiety disorder and social phobia were more likely to be associated with poor outcome. We discuss some potential mechanisms and implications in our findings.     

Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression

The objective of this study was to evaluate the longitudinal course of psychiatric disorders in children of parents with and without panic disorder and major depression as they transition through the period of risk from early to late childhood. Over a 5-year follow-up, we compared the course of psychiatric disorders in offspring of parents with panic disorder, major depression, or neither disorder. Subjects consisted of 233 offspring (from 151 families) with baseline and follow-up assessments. Subjects were comprehensively assessed with structured diagnostic interviews. Anxiety disorders at baseline were used to predict anxiety disorders and major depression at follow-up using stepwise logistic regression. Separation anxiety disorder significantly increased the risk for the subsequent development of specific phobia, agoraphobia, panic disorder, and major depression, even after parental panic and depression were covaried. Agoraphobia significantly increased the risk for subsequent generalized anxiety disorder. These findings suggest that separation anxiety disorder is a major antecedent disorder for the development of panic disorder and a wide range of other psychopathological outcomes, and that it increases the risk for subsequent psychopathology even among children already at high familial risk for anxiety or mood disorder.     

Anxiety disorders and onset of cardiovascular disease: The differential impact of panic,phobias and worry

Anxiety has been linked to onset of cardiovascular disease. This study examines the differential impact of types of anxiety (panic, phobia and worry) on 3-year onset of non-fatal cardiovascular disease (CVD). By investigating anxiety disorders as opposed to anxiety symptoms and by using a reliable diagnostic instrument to assess anxiety, limitations of previous studies are considered.5149 persons at risk for CVD were interviewed using the Composite International Diagnostic Interview. The panic-type included panic disorder and panic attacks; the phobic-type included agoraphobia and social phobia, and the worry-type included generalized anxiety disorder. CVD was self-reported and required treatment or monitoring by a doctor. Analyses were adjusted for sociodemographics, behavioral variables, and comorbid somatic and psychiatric disorders. During follow-up, 62 persons (1.2%) developed CVD. Baseline generalized anxiety disorder was strongly associated with onset of CVD (adjusted OR: 3.39). Further research should replicate findings and focus on biological underpinnings of this association.     

Differential patterns of lifetime multiple anxiety disorder comorbidity between Latino adults with bipolar I and major depressive disorders

BACKGROUND: To determine the lifetime rates of panic disorder, obsessive-compulsive disorder (OCD), social phobia, and posttraumatic stress disorder (PTSD) among adult Latino patients with major depressive disorder (MDD) and bipolar disorder (BPD), and whether there are dose-response relationships between loading for comorbid anxiety disorders, the probability of having BPD, and attributes of severity of illness. METHODS: In a public sector clinic for the indigent located in a semiclosed rural community, 187 consecutively presenting affectively ill Latino patients were evaluated by use of the Structured Clinical Interview for DSM-IV. Polarity and the lifetime prevalence of panic disorder, OCD, social phobia, and PTSD were determined. Logistic regression was used to test associations. Trends in positive predictive values (PPVs) and likelihood ratios were assessed to determine whether dose-response relationships existed between loading for comorbid anxiety disorders and the likelihood of having BPD as opposed to MDD, psychosis, suicidal ideation, and suicide attempts. Results: Of 187 subjects, 118 (63.1%) had MDD and 69 (36.9%) had BPD. The odds ratio of a patient with BPD, relative to MDD, of having panic disorder was 4.6 (p< .0001), OCD 7.6 (p< .0001), social phobia 6.0 (p< .0001) and PTSD 5.3 (p< .0001). The PPV of having BPD was 91.3% and of having psychotic features 83.0% if one had all four anxiety disorders. There was a dose-response relationship between loading for comorbid anxiety disorders and the likelihood of having had a suicide attempt (but not suicidal ideation). CONCLUSIONS: As previously reported by us for juvenile patients, Latino adults with BPD had a remarkably high risk of having each anxiety disorder relative to patients with MDD. The results indicate that the risk of having BPD, having a psychosis, and making a suicide attempt becomes increasingly great as the number of comorbid anxiety disorders increases. These data, which are consistent with the notion of anxious bipolarity, provide further support for a possible anxious diathesis in bipolar disorder.     

Chronicity,relapse, and illness--course of panic disorder,social phobia,and generalized anxiety disorder: findings in men and women from 8 years of follow-up

Anxiety disorders are chronic illnesses that occur more often in women than men. Previously, we found a significant sex difference in the 5-year clinical course of uncomplicated panic disorder that was attributable to a doubling of the illness relapse rate in women compared to men. However, we have not detected a sex difference in the clinical course of panic with agoraphobia, generalized anxiety disorder (GAD), or social phobia (SP), which are conditions generally thought to be more chronic than uncomplicated panic disorder. Given that a longer follow-up period may be required to detect differences in clinical course for more enduring illnesses, we conducted further analyses on this same cohort after a more protracted interval of observation to determine whether sex differences would emerge or be sustained. Data were analyzed from the Harvard/Brown Anxiety Research Program (HARP), a naturalistic, longitudinal study that repeatedly assessed patients at 6 to 12 month intervals over the course of 8 years. Data regarding remission and relapse status were collected from 558 patients and treatment was observed but not prescribed. Cumulative remission rates were equivalent among men and women with all diagnoses. Patients who experienced remission were more likely to improve during the first 2 years of study. Women with GAD continued remitting late into the observation period and experienced fewer overall remission events by 8 years. However, the difference in course failed to reach statistical significance. Relapse rates for women were comparable to those for men who suffered from panic disorder with agoraphobia, GAD, and SP. Again, initial relapse events were more likely to occur within the first 2 years of observation. However, relapse events for uncomplicated panic in women were less restricted to the first 2 years of observation and by 8 years, the relapse rates for uncomplicated panic was 3-fold higher in women compared with men. Anxiety disorders are chronic in the majority of men and women, although uncomplicated panic is characterized by frequent remission and relapse events. Short interval follow-up shows sex differences in the remission and relapse rates for some but not all anxiety disorders. These findings suggest important differences in the clinical course among the various anxiety disorders and support nosological distinctions among the various types of anxiety. It may be that sex differences in the clinical course of anxiety disorders hold prognostic implications for patients with these illnesses.     

Anxiety disorders in women.

Women have higher overall prevalence rates for anxiety disorders than men. Women are also much more likely than men to meet lifetime criteria for each of the specific anxiety disorders: generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), social anxiety disorder (SAD), posttraumatic stress disorder (PTSD), simple phobia, panic disorder, and agoraphobia. Considerable evidence suggests that anxiety disorders remain underrecognized and undertreated despite their association with increased morbidity and severe functional impairment. Increasing evidence suggests that the onset, presentation, clinical course, and treatment response of anxiety disorders in women are often distinct from that associated with men. In addition, female reproductive hormone cycle events appear to have a significant influence on anxiety disorder onset, course, and risk of comorbid conditions throughout a woman's life. Further investigations concerning the unique features present in women with anxiety disorders are needed and may represent the best strategy to increase identification and optimize treatment interventions for women afflicted with these long-neglected psychiatric disorders.     

Simple phobia as a comorbid anxiety disorder

This study sought to describe clinical and demographic characteristics differentiating patients with DSM-III-R simple phobias comorbid with one or more of five DSM-III-R index anxiety disorders as compared with those with the index diagnoses alone. From 711 subjects participating in a multicenter, longitudinal, naturalistic study of anxiety disorders, 115 subjects with comorbid simple phobias were compared with 596 subjects without simple phobias in terms of demographic data, comorbidity with other disorders, somatic and psychosocial treatment received, and quality of life. In addition, episode characteristics, types of simple phobias found, and course of illness were specified. Subjects with simple phobias had more additional comorbid anxiety disorders by history than did those without. Mean length of intake episode was 22.43 years and severity was typically moderate. Fears of heights and animals were the most commonly represented simple phobias. Subjects with uncomplicated panic disorder were less likely to have comorbid simple phobias than were subjects with other index diagnoses, and subjects with simple phobia were more likely to have comorbid posttraumatic stress disorder than were those without simple phobia. Subjects with and without simple phobias did not differ by somatic or psychosocial treatment received or in terms of quality of life. Simple phobia appeared in this study to be a chronic illness of moderate severity for which behavioral treatment methods of recognized efficacy were not being frequently utilized. Uncomplicated panic disorder may reflect some type of resistance to phobia development. Depression and Anxiety 7:105–112, 1998. © 1998 Wiley-Liss, Inc.     

Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study

This naturalistic European multicenter study aimed to elucidate the association between major depressive disorder (MDD) and comorbid anxiety disorders. Demographic and clinical information of 1346 MDD patients were compared between those with and without concurrent anxiety disorders. The association between explanatory variables and the presence of comorbid anxiety disorders was examined using binary logistic regression analyses. 286 (21.2%) of the participants exhibited comorbid anxiety disorders, 10.8% generalized anxiety disorder (GAD), 8.3% panic disorder, 8.1% agoraphobia, and 3.3% social phobia. MDD patients with comorbid anxiety disorders were characterized by younger age (social phobia), outpatient status (agoraphobia), suicide risk (any anxiety disorder, panic disorder, agoraphobia, social phobia), higher depressive symptom severity (GAD), polypsychopharmacy (panic disorder, agoraphobia), and a higher proportion receiving augmentation treatment with benzodiazepines (any anxiety disorder, GAD, panic disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder). The results in terms of treatment response were conflicting (better response for panic disorder and poorer for GAD). The logistic regression analyses revealed younger age (any anxiety disorder, social phobia), outpatient status (agoraphobia), suicide risk (agoraphobia), severe depressive symptoms (any anxiety disorder, GAD, social phobia), poorer treatment response (GAD), and increased administration of benzodiazepines (any anxiety disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder) to be associated with comorbid anxiety disorders. Our findings suggest that the various anxiety disorders subtypes display divergent clinical characteristics and are associated with different variables. Especially comorbid GAD appears to be characterized by high symptom severity and poor treatment response.     

Patterns of comorbidity in panic disorder and major depression: findings from a nonreferred sample

Previous findings in referred adult samples document major depression as having important moderating effects on the patterns of comorbidity for panic disorder and major depression. This study evaluated whether these patterns of comorbidity are moderated by referral bias. Panic disorder (PD) and major depression (MD) were used to predict the risk for comorbid psychiatric disorders and functional outcomes using data from a large sample of adults who had not been ascertained on the basis of clinical referral (N=1,031). Participants were comprehensively assessed with structured diagnostic interview methodology to evaluate childhood and adult comorbid psychiatric disorders. PD increased the risk for anxiety disorders, independently of MD. MD increased the risk for mania, antisocial personality disorder, psychoactive substance use disorder, disruptive behavior disorders, overanxious disorder, social phobia, and generalized anxiety disorder, independently of PD. These results extend to nonreferred samples' previously reported findings documenting that MD has important moderating effects on patterns of comorbidity for PD and indicate that patterns of comorbidity for PD are not due to referral bias.     

Patterns of comorbidity in panic disorder and agoraphobia.

Diagnoses of comorbid disorders were determined in a sample of 54 patients with panic disorder as defined in DSM-III-R. The sample was divided into the following three groups: (1) uncomplicated panic disorder (PDU); (2) panic disorder with mild agoraphobia (PDM); and (3) panic disorder with moderate to severe agoraphobia (PDA). In comparison with patients with PDU, patients with PDA had higher comorbidity rates in general, received multiple comorbid diagnoses more frequently, had a higher prevalence of major depression, dysthymia, social phobia, generalized anxiety disorder, and obsessive-compulsive disorder, and scored higher on most measures of self-rated psychopathology. These findings support the notion that PDA may be a disorder essentially different from PDU.     

Residual symptoms and comorbidity in panic disorder.

Background: The aim of this study was to assess the outcome of the comorbid conditions of panic disorder after 1 year of treatment, emphasizing the detection of residual symptoms and their relationship to other clinical variables. Methods: Subjects (N = 64) were assessed by the Structured Clinical Interview for DSM-III-R and the Eysenck Personality Questionnaire. Comorbidity with other disorders, scores on Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale were assessed at baseline and after 12 months. Criteria for residual anxiety/somatic symptoms were defined. Results: Reduction in generalized anxiety disorder rates accounted for a significant decrease in comorbidity at 1-year follow-up, with regard to baseline assessment. When the more severe symptoms of the disorder had remitted, a third of the patients referred physical symptoms with some concern over a fluctuating state of anxiety. The said symptoms were neither a recurrence of panic disorder nor did they account for other anxiety or somatoform disorders. Lower scores on extraversion predict higher risk of residual symptoms. Discussion: The persistence of residual anxiety/somatic symptoms in a third of the patients who apparently achieved a good response to treatment of panic disorder might characterize a minor form of chronic persistence of this condition. Conclusions: The subgroup of patients with residual symptoms would not be detectable by follow-up studies, which focus on the assessment of relapse of panic disorder by means of strictly defined diagnostic criteria.     

Antecedents to panic disorder in nonreferred adults

OBJECTIVE: Previous work has shown that childhood anxiety disorders are unique antecedents for panic disorder. The current study examined both childhood and adult comorbid disorders as potential antecedent disorders to panic disorder in a large sample of nonreferred adults. METHODS: Subjects were 1018 adults with (N = 58) and without (N = 960) panic disorder who were derived from a sample originally ascertained through family studies of probands with and without attention-deficit/hyperactivity disorder (ADHD); data were obtained from 1988 to 1996. Classification and regression trees (CART) analysis was used to examine anxiety and nonanxiety disorders antecedent to panic disorder. RESULTS: CART analysis showed that separation anxiety disorder, social phobia, and simple phobia were unique predictors of subsequent panic disorder. CONCLUSION: These results support and expand previously reported findings in referred samples documenting that comorbid anxiety disorders are unique antecedent risk factors for panic disorder.     

Panic disorder versus panic disorder with major depression: Defining and understanding differences in psychiatric morbidity

The present study examined the impact of comorbid major depressive disorder (MDD) on psychiatric morbidity, panic symptomatology and frequency of other comorbid psychiatric conditions in subjects with panic disorder (PD). Four hundred thirty-seven patients with PD were evaluated at intake as part of a multicenter longitudinal study of anxiety disorders; 113 of these patients were also in an episode of MDD. Patients were diagnosed by DSM-III-R criteria utilizing structured clinical interviews. The 113 PD/MDD patients were compared with the 324 remaining PD subjects regarding panic symptoms at intake, sociodemographic, quality of life and psychiatric morbidity variables. Differences in frequency of other comorbid Axis I psychiatric disorders were assessed at intake; personality disorders were evaluated twelve months after intake. The results revealed that PD/MDD patients exhibit increased morbidity and decreased psychosocial functioning as compared to PD patients. Personality disorders were more prevalent in the PD/MDD group at six month follow-up assessment; the PD/MDD group also had an increased frequency of posttraumatic stress disorder (PTSD) and more comorbid Axis I anxiety disorders as compared to the PD group. The total number and frequency of panic symptoms was highly consistent between the two patient groups. Depression and Anxiety 5:12–20, 1997. © 1997 Wiley-Liss, Inc.     

Personality disorders in patients with panic disorder: association with childhood anxiety disorders, early trauma, comorbidity, and chronicity.

The rates of comorbid personality disorders in patients with panic disorder are reported to be elevated, have an adverse impact on the response to treatment, and increase the likelihood of relapse on treatment discontinuation. We examined the rates of personality disorders in panic disorder patients in a longitudinal, naturalistic study of panic disorder. Of 100 panic disorder patients studied, 42 met criteria for at least one personality disorder as determined by the Personality Disorder Questionnaire-Revised (PDQ-R). The presence of a personality disorder as determined by the PDQ-R was associated with a past history of childhood anxiety disorders, comorbidity with other anxiety disorders and depression, and a chronic, unremitting course of panic disorder in adulthood. The presence of a personality disorder in these patients was not significantly associated with a history of physical or sexual abuse in childhood. Our findings support the notion that an anxiety diathesis, demonstrated by significant difficulties with anxiety in childhood, influences the development of apparent personality dysfunction in panic patients. In other cases, personality pathology may reflect the presence of comorbid anxiety disorders or depression. The association of personality disorder in panic patients with a more unremitting course of illness underscores the importance of axis II pathology in understanding the longitudinal course of panic disorder.     

Anxiety disorders and substance use disorders: different associations by anxiety disorder

Anxiety disorders (ADs) and substance use disorders (SUDs) often occur together, but the strength of this association and their apparent order of onset differ across studies. The goals of this study were to examine: (1) which ADs were associated with which SUDs, and (2) among people who experienced both an AD and a SUD, which disorder had an earlier onset. Lifetime diagnoses from the National Comorbidity Survey-Replication (n=9282) were used. Social phobia, generalized anxiety disorder, panic disorder, and agoraphobia were positively associated with all SUDs. Among people with both an AD and a SUD, the order of onset differed by anxiety type: social phobia nearly always had an onset prior to any SUD; panic disorder and agoraphobia tended to occur prior to some SUDs; and generalized anxiety disorder tended to occur after the onset of at least one SUD. Therefore, all ADs are positively associated with SUDs, but ADs differ in the timing of their onset relative to comorbid SUDs.     

Infrequency of "pure" GAD: impact of psychiatric comorbidity on clinical course.

The widespread occurrence of psychiatric comorbidity among patients with generalized anxiety disorder (GAD) has been well documented. However, there is a paucity of studies examining the impact comorbid disorders have on the clinical course of GAD. In this study, 179 patients with GAD at intake, 12 patients with a past history of GAD, and 109 patients who subsequently onset a first episode of GAD during the course of follow-up were followed for 8 years in this naturalistic, prospective study of anxiety disorders. Results indicate that comorbid anxiety, mood, and substance use disorders are very common with GAD and increased during follow-up. For example, 39% of participants with GAD also had a comorbid diagnosis of major depressive disorder at intake and increased to 65% at 4 years and 74% at the 8-year follow-up. Inspection of "pure" cases of GAD indicated that out of 20 patients with GAD alone at intake, all but 1 went on to develop some comorbidity. Results also indicate that being in episode of comorbid MDD or panic disorder with agoraphobia decreased the probability that a subject would remit from their GAD. The findings highlight the need for such long-term, prospective research since results show that patients with GAD at intake had increasing risk for developing other mental disorders during subsequent follow-ups. Additionally, results of such high comorbidity and the impact of these comorbid disorders on the clinical course of GAD should have a notable impact on research into the treatment of GAD.     

Clinical and subthreshold panic disorder

Background: Panic disorder (PD) is a highly prevalent and disabling condition, and subthreshold cases may be even more prevalent. This study examined psychiatric comorbidities, work functioning, and health‐care utilization of individuals with subthreshold panic. The purpose of this study was to add to the accumulating evidence of significant comorbidity and disability associated with subthreshold PD. Methods: Data are drawn from the Health Care for Communities study, a national household survey of the United States' adult, civilian, noninstitutionalized population (N=9585). Data assessing psychiatric disorders, employment and work productivity, and health‐care utilization were collected. Seven categories of panic and subthreshold panic were created. Results: The prevalence of clinical and subthreshold panic in the general population was 40%. Subthreshold panic was associated with increased odds of several comorbid disorders, including depression, dysthymia, psychosis, generalized anxiety disorder, bipolar disorder, and alcohol and drug use disorders. Subthreshold panic was also associated with greater likelihood of health‐care service utilization but not with the intensity of mental health services. Conclusion: Psychiatric comorbidities and health‐care utilization are common among patients with subthreshold panic. The relationship between varying degrees of panic symptomology and other mental health problems and indices of functioning impairment warrants further investigation. These results inform further research focusing on the course of subthreshold PD and its impact on quality of life. Depression and Anxiety, 2010. © 2009 Wiley‐Liss, Inc.