Bipolar I patients scored higher on harm avoidance, lower on self-directedness, and higher on self-transcendence compared to controls. The results indicate that Bipolar I subjects do possess personality traits that are significantly different from non-ill individuals. Only a prospective, longitudinal study may determine whether these traits mark a vulnerability to the disorder, or represent the scarring effect of affective episodes and chronic subsyndromal symptoms.
Bipolar I patients scored higher on harm avoidance, lower on self-directedness, and higher on self-transcendence compared to controls. The results indicate that Bipolar I subjects do possess personality traits that are significantly different from non-ill individuals. Only a prospective, longitudinal study may determine whether these traits mark a vulnerability to the disorder, or represent the scarring effect of affective episodes and chronic subsyndromal symptoms.
Bipolar I patients scored higher on harm avoidance, lower on self-directedness, and higher on self-transcendence compared to controls. The results indicate that Bipolar I subjects do possess personality traits that are significantly different from non-ill individuals. Only a prospective, longitudinal study may determine whether these traits mark a vulnerability to the disorder, or represent the scarring effect of affective episodes and chronic subsyndromal symptoms.
Temperament and character dimensions in bipolar I disorder:
A comparison to healthy controls
Shay T. Loftus * , Jessica L. Garno, Judith Jaeger, Anil K. Malhotra The Zucker Hillside Hospital, Department of Psychiatry Research, North Shore Long Island Jewish Health System, 75-59 263rd Street, Glen Oaks, NY 11004, United States Received 29 January 2007; received in revised form 11 November 2007; accepted 15 November 2007 Abstract Research on phenotypic markers of vulnerability to bipolar disorder has focused on the identication of personality traits uniquely associated with the illness. To expand knowledge in this area, we compared Cloningers seven temperament and character dimensions in 85 euthymic/subsyndromal bipolar I inpatients and outpatients and 85 age and sex matched community controls. We also examined associations between Cloningers personality traits and mood state in the patient group. Bipolar subjects were administered the Struc- tured Clinical Interview for DSM-IV (SCID), Hamilton Rating Scale for Depression, and Clinician-Administered Rating Scale for Mania. Controls received the SCID, a family psychiatric history questionnaire, and urine toxicology screen to conrm healthy status. Both groups competed the 240-item Temperament and Character Inventory (TCI). A multivariate analysis of covariance, accounting for demographic factors, was conducted to compare the groups on the TCI. Bipolar I patients scored higher on harm avoidance, lower on self-directedness, and higher on self-transcendence compared to controls. Harm avoidance and self-directedness were correlated with residual depressive symptoms positively and negatively, respectively; persistence was correlated with residual manic symptoms; and self- transcendence was correlated with residual psychotic symptoms in patients. The results indicate that bipolar I subjects do possess per- sonality traits that are signicantly dierent from non-ill individuals. However, only a prospective, longitudinal study may determine whether these traits mark a vulnerability to the disorder, or represent the scarring eect of aective episodes and chronic subsyndromal symptoms. 2007 Elsevier Ltd. All rights reserved. Keywords: Bipolar disorder; Personality; Temperament; Character; State-trait 1. Objectives of the study Investigators have identied personality traits that may represent markers of bipolar illness (Engstrom et al., 2004; Nowakowska et al., 2005; Solomon et al., 1996), mod- ify its course (Lozano and Johnson, 2001; Swendsen et al., 1995) or inuence treatment response (Maj et al., 1984). The relationship of personality to aective disorders is com- plex, however, since many traits appear to be unstable, varying with changes in symptom levels (Hirshfeld et al., 1983; Peselow et al., 1995). This phenomenon, known as the state-trait eect, can result in the exaggeration of path- ological personality traits during acute symptomatic peri- ods as well as during periods of relative stability. Adding to the complexity, multiple aective episodes may have a scarring eect, leading chronically ill patients to report exaggerated traits compared to those in the early stages of illness (Hirschfeld et al., 1989; Dunayevich et al., 1996). A widely used trait model in bipolar research currently is Cloninger et al.s (1991, 1993, 1994) seven-factor biosocial model of personality, comprised of four dimensions of tem- perament and three dimensions of character. The tempera- ment dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) are posited to be independent, 0022-3956/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2007.11.005 * Corresponding author. E-mail address: loftus.shay@yahoo.com (S.T. Loftus). JOURNAL OF PSYCHIATRIC RESEARCH Available online at www.sciencedirect.com Journal of Psychiatric Research 42 (2008) 11311136 www.elsevier.com/locate/jpsychires biologically-based predispositions that are stable through- out life. Novelty seeking reects a tendency to respond actively to novel cues of reward or punishment. Harm avoidance is a trait leading to behaviors that avoid aversive stimuli. Reward dependence represents an inclination to respond strongly to cues of social reward; and persistence maintains previously established behaviors. Cloninger et al.s (1993, 1994) character dimensions (self directedness, cooperativeness, and self-transcendence), in contrast, evolve throughout the lifespan, and are inuenced by social and environmental factors. Self-directedness is the ability to adapt ones behaviors to achieve chosen goals. Cooperativeness is a tendency to empathize with, accept and cooperate with others. Finally, self-transcendence cor- responds to an identication or spiritual union with nature or the universe. Studies examining the temperament dimensions in bipo- lar, unipolar, and healthy subjects using the Tridimensional Personality Questionnaire (Cloninger, 1987) have yielded inconsistent results. Young and colleagues (1995) found recovered bipolar outpatients higher in novelty seeking than both unipolar depressives and age-matched controls, while both patient groups were higher in harm avoidance than healthy subjects. Osher et al. (1996) reported that euthymic outpatients scored lower in persistence and higher in harm avoidance and reward dependence than population norms. However, in a replication study (Osher et al., 1999) comparing euthymic outpatients to sex, but not age-matched controls, bipolar patients scored lower in nov- elty seeking and persistence. The dierence in novelty seek- ing in the latter study was explained by the higher mean age of patients, as novelty seeking had been observed previ- ously to decrease with age in a large probability sample (Cloninger et al., 1991). In a sample of rst-episode psychotic inpatients, Stra- kowski et al. (1992) found that bipolar manic subjects had lower harm avoidance scores than depressive, mixed, and nonaective subjects. Further, a positive correlation was observed between harm avoidance and depressive symptoms; and a negative correlation, between harm avoidance and manic symptoms, suggesting that harm avoidance was vulnerable to state eects. Engstrom and colleagues (2004) administered the Tem- perament and Character Inventory (TCI; Cloninger et al., 1993, 1994) to euthymic bipolar I and II outpatients and found bipolar subjects higher in harm avoidance, and lower in reward dependence, self-directedness, and cooperative- ness than matched controls. The bipolar I subgroup speci- cally was lower in reward dependence and cooperativeness compared to controls, although eect sizes were weak. Now- akowska et al. (2005), also using the TCI, found euthymic bipolar I, bipolar II, and bipolar NOS outpatients higher in novelty seeking, harm avoidance, and self-transcendence, and lower in self-directedness than healthy subjects. These data suggest that bipolar disorder may be associ- ated with increased harmavoidance, increased novelty seek- ing, decreased persistence, and decreased self-directedness. However, studies of Cloninger et al.s (1993) dimensions are dicult to compare due to sample selection biases, sam- ple size dierences, and other methodological variation. Some investigators have assessed inpatients (Strakowski et al., 1992) while others have assessed outpatients (Osher et al., 1999; Engstrom et al., 2004; Nowakowska et al., 2005; Young et al., 1995). Not all have used standardized diagnostic interviews to conrm a bipolar diagnosis (Osher et al., 1999). Operational denitions of euthymia have var- ied across studies (Osher et al., 1996; Engstrom et al., 2004). Bipolar I and II patients have been combined in analyses (Nowakowska et al., 2005) although their TCI proles are not congruent, especially on the lower order personality dimensions (Engstrom et al., 2004). Patients with substance abuse comorbidities have been excluded from some samples (Engstrom et al., 2004; Nowakowska et al., 2005). Finally, investigators do not consistently covary for demographic and clinical factors known to inuence TCI trait scores, such as age, sex, educational level, and psychiatric symp- toms (Mendlowicz et al., 2000). The aim of the present study was to evaluate dierences in TCI personality dimensions between recently recovered bipolar I patients and healthy subjects, while controlling for potentially confounding variables; and to examine whether the TCI dimensions are independent of concurrent mood state. 2. Methods and materials 2.1. Participants The sample consisted of 85 bipolar I inpatients (n = 45) and outpatients (n = 40) and 85 age and sex matched healthy controls recruited from the community. Bipolar patients were a subgroup among a larger cohort of partici- pants in a two-year naturalistic study of the relationship of neuropsychological decits to functional recovery in bipo- lar disorder. Included in the larger cohort were individuals 1859 years old who were hospitalized for an acute aective episode. Exclusion criteria were mental retardation, neuro- logical disease, serious medical illness, and lack of uency in the English language. Two-thirds of the patient sample (n = 53, 62.4%) had at least one comorbid axis I disorder; 37.6% (n = 32) reported two or more. The most common comorbid diagnoses were substance abuse or dependence (n = 46, 54.1%) followed by anxiety disorders (n = 16, 18.8%). Patients mean age of ill- ness onset was 22.52 years (SD = 6.35) and the average duration of illness was 12.14 years (SD = 9.39). The mean number of lifetime hospitalizations was 6.14 (SD = 5.19). All subjects provided written informed consent after the study procedures were fully explained to them. 2.2. Instruments Bipolar patients were assessed with the Structured Clin- ical Interview for DSM-IV-Patient Edition (SCID-I/P; 1132 S.T. Loftus et al. / Journal of Psychiatric Research 42 (2008) 11311136 First et al., 1996) by trained masters and doctoral-level research assistants. Information gathered from the patient, available colaterals, and the medical record was compiled by the interviewer into a detailed case summary. This case summary was presented to a committee of three senior investigators who then rendered a consensus SCID diagno- sis. Healthy controls were screened with the Structured Clinical Interview for DSM-IV-Non-Patient Edition (SCID-I/NP; First et al., 2001) to exclude lifetime axis I disorders. In addition, they had no rst-degree relatives with a history of psychiatric illness and presented with a negative urine toxicology test for illicit substances. All participants were administered the TCI, a 240 item true/false questionnaire measuring Cloninger et al.s (1993, 1994) four dimensions of temperament (novelty seeking, harm avoidance, reward dependence, and persis- tence) and three dimensions of character (self-directedness, cooperativeness, and self-transcendence). Each of the seven higher order dimensions is composed of three to ve lower order facets or subcomponents of personality, yielding 25 subscales in all. For example, the temperament factor, nov- elty seeking is composed of four subcomponents including exploratory excitability, impulsiveness, extravagance, and disorderliness; while the character dimension of self-direct- edness is described by the lower order traits of responsibil- ity, purposefulness, resourcefulness, self-acceptance, and congruent second nature. Concurrent aective symptoms were assessed monthly in patients using the 17-item version of the Hamilton Rat- ing Scale for Depression (HRSD-17; Hamilton, 1960) and the Clinician-Administered Rating Scale for Mania (CARS-M; Altman et al., 1994). Bipolar patients com- pleted the TCI when their symptoms had improved to within the mild range (dened by scores of 17 on the HRSD-17 and 15 on the mania subscale (items 110) of the CARS-M) to limit the degree to which state-related fac- tors would aect personality ratings. The mean HRSD-17 score was 7.57 (SD = 4.92) and the mean CARS-M total score was 6.83 (SD = 5.08). No subject met syndromal cri- teria for a manic, mixed, hypomanic, or depressive episode at the time the TCI was administered. 2.3. Statistical analyses Independent t-tests and Pearson correlations were con- ducted to examine the associations between age, sex, and educational attainment and the seven TCI dimensions in both subject groups. A multivariate analysis of covariance (MANCOVA) was then performed to examine the dier- ences between bipolar I patients and healthy controls on the seven TCI dimensions, covarying for the eects of the demographic factors. To evaluate the state dependence of the instrument, Pearson correlations were calculated between the seven TCI dimensions and the HRSD-17 and CARS-M. A MANCOVA controlling for demographic factors was used to compare subjects treated for a manic vs. a depressive episode at the index hospitalization on TCI traits. A second MANCOVA controlling for demographic factors was used to compare inpatient vs. outpatient subjects on TCI traits. To control for multiple comparisons, a Bonferroni cor- rected alpha was adopted (.05/7 = .007). 3. Results 3.1. Relationship of the TCI to demographic variables There were no signicant dierences between the patient and control groups with respect to age (34.82 10.19 vs. 34.53 10.25; t = .18, p = .85) and sex (42 vs. 40 females; v 2 = .09, p = .76). Control participants, however, were more highly educated than patients on average (15.32 1.77 vs. 14.26 2.47 years; t = 3.21, p = .002). There were no signicant relationships between the seven TCI dimensions and the three demographic factors in the patient group. In the control group, females were sig- nicantly higher in self-directedness than males (36.60 6.22 vs. 32.04 7.53; t = 3.01, p = .003). 3.2. Comparison of the TCI in bipolar I patients and healthy controls A MANCOVA comparing patients and controls on the seven dimensions with diagnostic group as the independent variable and age, sex, and education as covariates yielded a main eect for group (F = 3.95, p < .001). Bipolar patients were signicantly higher in harm avoidance, lower in self- directedness, and higher in self-transcendence compared to controls. Eect sizes were large for these three personal- ity traits. Post hoc analyses using a Bonferroni corrected alpha of p < .002 (.05/25) revealed that patients and controls dif- fered signicantly on 9 of the 25 of the lower order person- ality dimensions. Three of the four harm avoidance subscales, anticipatory worry, fear of uncertainty, and fati- gability, were higher among patients than controls. Among the self-directedness subscales, three of the ve scales were lower among patients including responsibility, resourceful- ness, and congruent second nature. Among the coopera- tiveness subscales, only helpfulness was signicantly lower in patients. Finally, among the self-transcendence subscales, bipolar patients endorsed higher self-forgetful- ness compared to controls. Table 1 summarizes the means and standard deviations of the TCI scales and subscales, and results of the multivariate analysis. 3.3. The state dependency of the TCI in bipolar I patients Pearson correlations demonstrated that harm avoidance was positively correlated with depressive symptoms (r = 0.47, p < .001) and that self-directedness was nega- tively correlated with depressive symptoms (r = 0.47, p < .001). None of the seven scales was signicantly corre- lated with the CARS-M total score; however, among the S.T. Loftus et al. / Journal of Psychiatric Research 42 (2008) 11311136 1133 CARS-M subscales, persistence was positively correlated with the mania subscale (items 110, M = 5.02 3.84; r = .30, p = .006) and self-transcendence was positively correlated with the psychosis subscale (items 1115, M = 1.99 3.03; r = .29, p = .007). Over half of the patient group (n = 52, 61.2%) was most recently hospitalized for an episode of mania; approxi- mately one-third (n = 25, 29.4%) had been hospitalized for an episode of depression, and the remainder (n = 8, 9.4%) had been treated for a mixed episode. Patients most recently hospitalized for mania were lower in harm avoid- ance (16.00 7.01 vs. 21.64 7.59; F = 8.80, p = .004), and higher in self-directedness (30.31 8.65 vs. 22.84 8.57; F = 10.71, p = .002) than depressed patients, after controlling for demographic factors. Fifty-three percent (n = 45) of patients completed the TCI during the index hospitalization. The mean number of months between hospitalization and TCI completion was 3.29 (SD = 5.74). Patients who completed the TCI while hospitalized were signicantly higher in persistence than patients who completed the TCI after discharge (5.78 1.61 vs. 4.53 2.12; F = 9.73, p = .003). 4. Discussion This study compared bipolar I patients whose symptoms had recently improved to euthymic/subsyndromal status with healthy controls on temperament and character dimensions. Patients responses reected higher harm avoidance, lower self-directedness, and higher self-tran- scendence scores than controls. Thus by their own report, they appeared more fatigable, shy, worry prone, and pessi- mistic. They endorsed less reliable and resourceful behav- iors, which may lead them to be less able to eciently pursue goals. Finally, they armed feeling highly creative and spiritual. These results generally concur with those of other research groups (Young et al., 1995; Nowakowska et al., 2005). All three of the traits distinguishing patients were corre- lated with concurrent symptoms raising the question of whether the TCI is a state-dependent measure. Our ndings are consistent with studies of depressed samples that have reported signicant correlations between harm avoidance and depression and inverse relationships between depression and self-directedness (Hansenne et al., 1999; Hirano et al., Table 1 Comparison of TCI dimensions in 85 bipolar I patients and 85 matched controls Bipolar patients mean (SD) Healthy controls mean (SD) MANCOVA F-ratio df = (1, 165) P d/s Novelty seeking 20.27 (5.76) 19.53 (4.87) 0.11 0.75 0.14 Exploratory excitability 6.44 (2.05) 7.05 (2.04) 4.69 0.03 Impulsiveness 4.35 (2.36) 3.49 (2.11) 3.92 0.05 Extravagance 5.08 (2.04) 4.85 (1.81) 0.03 0.85 Disorderliness 4.40 (2.00) 4.14 (1.88) 0.29 0.59 Harm avoidance 17.73 (7.63) 11.41 (6.68) 26.63 <0.001 0.88 Anticipatory worry 5.12 (2.77) 3.27 (2.40) 17.49 <0.001 Fear of uncertainty 4.44 (1.74) 3.08 (1.77) 24.16 <0.001 Shyness 3.86 (2.37) 2.66 (2.38) 7.53 0.007 Fatigability 4.32 (2.68) 2.40 (2.28) 19.28 <0.001 Reward dependence 15.96 (3.60) 15.75 (3.90) 0.41 0.53 0.06 Sentimentality 7.25 (2.19) 6.59 (2.13) 3.41 0.07 Attachment 5.14 (1.93) 5.32 (2.07) 0.09 0.76 Dependence 3.58 (1.43) 3.85 (1.45) 0.55 0.46 Persistence 5.19 (1.96) 4.95 (1.82) 1.28 0.26 0.12 Self-directedness 27.62 (9.05) 34.19 (7.27) 20.94 <0.001 0.80 Responsibility 5.48 (2.04) 6.87 (1.49) 20.85 <0.001 Purposefulness 5.25 (2.19) 6.15 (1.79) 7.52 0.007 Resourcefulness 3.19 (1.40) 4.15 (1.30) 14.46 <0.001 Self-acceptance 6.21 (2.85) 7.11 (3.07) 1.70 0.20 Congruent second nature 7.49 (3.17) 9.91 (2.26) 27.81 <0.001 Cooperativeness 31.08 (6.22) 33.18 (5.31) 2.55 0.11 0.36 Social acceptance 6.54 (1.45) 6.99 (1.49) 2.31 0.13 Empathy 5.20 (1.34) 5.48 (1.35) 0.86 0.35 Helpfulness 5.33 (1.30) 6.00 (1.08) 11.15 0.001 Compassion 7.71 (2.26) 7.79 (2.34) 0.15 0.70 Pure-heartedness 6.31 (1.93) 6.92 (1.42) 2.14 0.15 Self-transcendence 16.32 (6.25) 12.21 (6.96) 16.13 <0.00 0.62 Self-forgetfulness 5.74 (2.81) 3.80 (2.48) 21.17 <0.001 Transpersonal Identication 3.41 (2.08) 2.57 (2.20) 7.37 0.007 Spiritual acceptance 7.16 (2.98) 5.85 (3.57) 6.96 0.009 1134 S.T. Loftus et al. / Journal of Psychiatric Research 42 (2008) 11311136 2002; Richter et al., 2000). Supporting the position that these particular traits may be state dependent, reductions in depressive symptoms have been accompanied by decreases in harm avoidance and increases in self-directedness when measured in the same patients longitudinally (Chien and Dunner, 1996; Hirano et al., 2002; Joe et al., 1993). High harm avoidance has been the most consistent nd- ing across bipolar studies and appears to be associated with the subsyndromal depression experienced by many patients in interepisode periods (Judd et al., 2002). Harm avoidance is posited to be linked to serotonin by Cloninger (1987), which is implicated in depressive states. Serotonergic dys- regulation may underlie both the chronic depressive symp- toms and harm avoidant tendencies found in this population. Akiskal and colleagues (1983) delineate four possible relationships between personality and aective ill- ness. To illustrate with harm avoidance: high harm avoid- ance may (a) signal a vulnerability to developing an aective disorder; (b) result from current state related changes in mood; (c) represent a scarring eect of illness in which the elevation remains after the resolution of symp- toms or; (d) independently modify the expression of symptoms. Lower self-directedness in patients as compared to con- trols was also found by Nowakowska et al. (2005). How- ever, lower self-directedness is not specic to bipolar disorder. It extends to other psychiatric samples (Klump et al., 2004; Lyoo et al., 2001) and may be an artifact of ill- ness. Higher levels of depression may also explain the lower self-directedness scores in our sample, but we could not clarify the role of current symptoms in contributing to group dierences as symptom levels were not assessed in the healthy subjects. In addition, we found severity of psychosis related to self-transcendence. Bipolar patients arming high self- transcendence may give unusual, imaginative and idiosyn- cratic interpretations to events that are associated with psychotic thought processes and/or the hyperreligious ide- ation accompanying mania. According to Cloninger et al.s (1994) character theory, high self-transcendence in the presence of high self-directedness leads to a mature creativ- ity and spirituality. However, as noted by Bayon et al. (1996), who found self-transcendence positively correlated with the Millon scales, delusions and mania, high self-transcendence in the presence of low self- directedness may suggest a proneness to psychosis. Thus the greater self- transcendence scores in our sample may reect residual symptoms rather than the transpersonal consciousness pro- posed by Cloninger et al. (1993, 1994). Our results dier markedly from those of Engstrom et al. (2004), who reported dierences between bipolar I patients and controls on reward dependence and coopera- tiveness only. Apart from the state-dependency issue already noted, sample selection might account for the opposing results. Engstrom et al. (2004) assessed euthymic, lithium monotherapy outpatients who did not present with a substance abuse disorder. Our sample, in contrast, was comprised of recently recovered individuals, 62% of whom suered from an axis I comorbidity (with 54% carrying a lifetime substance abuse or dependence diagnosis). The bipolar subjects in our study likely presented with more complicating illness features, which could be the result of a more pronounced temperamental prole or cause greater scarring eects on personality. We did not conrm others ndings of either higher (Nowakowska et al., 2005; Young et al., 1995) or lower (Osher et al., 1999) novelty seeking, and lower persistence (Osher et al., 1996; Osher et al., 1999) in bipolar patients. This lack of replication might be due to dierences in cur- rent mood state among the samples, the limited sample sizes used in previous studies, or the neglect to control for demographic variables that have demonstrated rela- tionships with the TCI (Mendlowicz et al., 2000). Although not a temperamental dierence between patients and con- trols here, we found persistence higher in inpatients vs. out- patients and signicantly correlated with manic symptoms. The perseverant and goal directed behaviors characteristic of high persistence appear to increase when patients are in a manic or hypomanic state. Our study is limited by its cross-sectional design, the het- erogeneity of the bipolar group (i.e., inpatient and outpa- tient; high degree of comorbidity), and lack of symptom measures among the healthy subjects. Future studies that are both prospective and longitudinal in nature, assess patients when euthymic, and account for demographic and clinical variables aecting personality measurement are necessary to disentangle the relationship between state and trait. Such designs may determine whether there is a temperamental vulnerability to developing a mood disor- der as a sibling pair study indicates (Farmer et al., 2003), whether mood disorders inuence personality, or whether there exists a complex interplay of both processes on neu- rodevelopment over the lifespan. Role of the funding source Funding for this study was provided by NIMH Grant R01MH 60904-02 (Judith Jaeger, Ph.D., M.P.A., Principal Investigator) and the Stanley Medical Research Institute. The NIMH and the Stanley Medical Research Institute had no role in the study design; in the collection, analysis, and the interpretation of the data; in the writing of this report; and in the decision to submit it for publication. Contributors This study was based upon Dr. Loftuss psychology doc- toral dissertation and was an addition to Dr. Jaegers NIMH grant entitled, Targeting Disabilities for Rehabil- itation in Bipolar Disorder. Dr. Loftus undertook the lit- erature review and designed the study. Dr. Loftus and members of Dr. Jaegers sta collected the patient data. Dr. Malhotra provided the healthy control data. Dr. Lof- tus and Dr. Garno ran the statistical analyses and wrote S.T. Loftus et al. / Journal of Psychiatric Research 42 (2008) 11311136 1135 the manuscript. Dr. Jaeger and Dr. Malhotra provided guidance on subsequent drafts. All authors have approved of the nal manuscript. Conicts of interest Dr. Shay Loftus, Dr. Jessica Garno, Dr. Judith Jaeger, and Dr. Anil Malhotra declare that they have no conicts of interest that could inappropriately inuence their work and the research report submitted here. Acknowledgements The authors wish to thank Drs. 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