REGULAR ARTICLES. Informant Reports of Changes in Personality Predict Dementia in a Population-Based Study of Elderly African Americans and Yoruba

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1 REGULAR ARTICLES Informant Reports of Changes in Personality Predict Dementia in a Population-Based Study of Elderly African Americans and Yoruba Valerie Smith-Gamble, M.D., Olusegun Baiyewu, M..B., B.S. Anthony J. Perkins, M.S., Oye Gureje, M.B., B.S., Ph.D. Kathleen S. Hall, Ph.D., Adesola Ogunniyi, M.B., Ch.B. Siu L. Hui, Ph.D., Hugh C. Hendrie, M.B., Ch.B. Objective: The authors did a longitudinal, population-based survey of African Americans in Indianapolis, Indiana, and Yoruba in Ibadan, Nigeria, using the Community Screening Interview for Dementia to assess the predictive value of informant reports of changes in personality on incident dementia and Alzheimer disease. Methods: In all, 3,021 subjects had informants reports of changes in personality and dementia status (2,084 subjects residing in Ibadan and 937 subjects residing in Indianapolis). Results: After adjusting for demographic, cognitive, and functional characteristics in two markedly different populations, socioeconomically and culturally, subjects with changes in personality had approximately twice the odds of having dementia as subjects with no change in personality. Conclusion: The finding that in two markedly different populations, personality change is a significant predictor of future dementia, independent of cognition and functional status, should make clinicians particularly sensitive to these reports when they occur in their elderly patients. (Am J Geriatr Psychiatry 2002; 10: ) The dementing disorders, particularly Alzheimer disease (AD), represent a major public health burden for the United States. It is currently estimated that 4 million people have AD in the United States, and that number will increase to 14 million by the year Approximately $100 billion is spent annually in the United States on the disease. 2 However, new advances in our understanding and treatment of AD now make it potentially treatable. Early diagnosis of AD becomes increasingly important and may possibly both delay its progression and decrease its cost. 3 Early clinical detection of AD, including screening efforts, have focused on measuring cognitive decline. Yet, noncognitive behavioral symptoms are common in Received June 14, 2001; revised September 27, 2001; accepted December 19, From the Departments of Psychiatry (VSG,KSH,HCH),Medicine (SLH,HCH), and The Regenstrief Institute Center on Aging Research (AJP,SLH,HCH), Indiana University School of Medicine, and the Departments of Psychiatry (OB,AJP,OG) and Neurology (AO), University of Ibadan (Nigeria). Address correspondence to Dr. Smith-Gamble, Department of Psychiatry, Indiana University School of Medicine, 541 Clinical Drive, Rm. 394, Indianapolis, IN Valerie.smith-gamble@med.va.gov Copyright 2002 American Association for Geriatric Psychiatry Am J Geriatr Psychiatry 10:6, November-December

2 Personality Changes and Dementia the dementias. Both the 10th Revision of the International Classification of Disease (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised (DSM-III-R) include personality changes as part of the diagnostic criteria for dementia. 4,5 The DSM-IV lists personality change under associated features; however, personality change is not included in the criteria for diagnosis. 6 A variety of personality changes have been described in AD patients. These have included accentuation of premorbid personality characteristics; coarsening of affect; increased neuroticism, apathy, and eccentricity; decreased extroversion; and changes in agreeableness Some studies have suggested that these personality changes may precede evidence of cognitive decline. 7,10 However, most of these studies have been retrospective in nature. In a prospective study by Jacomb et al., 11 personality change, as defined by the Canberry Interview for the Elderly (CIE), was shown to be positively correlated with cognitive impairment. Since 1992, research teams from Indiana University and the University of Ibadan, using identical methodologies, have been collaborating on studies of the prevalence and incidence of dementia in elderly African Americans and Yoruba. As part of the screening phase of the study, informant reports on personality change are recorded. This article reports on the possible predictive value of personality change on incidence of dementia and AD in these two populations. METHODS Study Design and Study Populations The data for this study come from the Indianapolis Ibadan Dementia Project. In , we conducted a population-based survey of African Americans in Indianapolis and Yoruba in Ibadan, Nigeria, who were age 65 or older. The sampling and data collection have been described elsewhere. 18,19 For Indianapolis, a 60% simple random sample of households was taken in a geographic target area of 29 contiguous census tracts in which African Americans represent 80% of the population in the 1990 U.S. Census. Interviewers approached 7,590 households; 4,915 households were ineligible because there were no residents age 65 years or older, and 383 households had no African Americans. A total of 2,582 eligible persons were identified, and 2,212 interviews were completed. For Ibadan, Nigeria, a total population survey was carried out by means of door-to-door screening in a geographically defined area. The household enumeration and census was completed for 3,489 households, and interviews were completed with 2,487 of 2,535 eligible individuals. This project was approved by the Indiana University School of Medicine Institutional Review Board and by the University of Ibadan Institutional Review Board. All participants (or legal guardians) gave written informed consent at each phase of the study. Participants were paid a small sum of money at each phase of the study. We used a two-phase design to ascertain dementia status in the two samples. In the first phase, the Community Screening Instrument for Dementia (CSI D ) was administered. The CSI D consists of a brief cognitive examination and health history interview with the participant and an interview with an informant who has knowledge of the participant s daily functioning and general health. It includes demographic information on age, gender, years of education, and physical disabilities suffered by the subject that impair activities of daily living. Low education was defined as 8 years for Indianapolis and no-education in Ibadan. The cognitive scores, functional scores, and the number of subjects with physical disabilities causing impairment were used in our analysis. The process in the development of the CSI D, including item selection, translation, and backtranslation, small pilot testing for acceptability, and large pilot testing to develop normative values, has been described elsewhere. 20,21 Before the field work was done, interviewers attended a 2-week training course to ensure consistency in administration. High interrater reliability was obtained, with a kappa of 1 for almost all items. On the basis of the extensive earlier fieldwork with the CSI D, cut-off scores were used to characterize each screening subject as having low, medium, or high probability of showing dementia. 20,21 Subjects with a low probability of dementia were classified as good performers, and subjects with a high probability of dementia were classified as poor performers. The percentage of subjects in Indianapolis and Ibadan in each of these performance groups was quite comparable: good performance, Indianapolis, 80.6%; Ibadan, 82.2%; intermediate performance, Indianapolis, 7.6%; Ibadan, 7.7%; poor performance, Indianapolis, 11.8%; Ibadan, 10.1%. In the second phase, subjects were sam- 2 Am J Geriatr Psychiatry 10:6, November-December 2002

3 Smith-Gamble et al. pled for the clinical assessment according to their CSI D performance category. All subjects from the poor performance group were selected for clinical assessment. To determine incident cases, subjects were randomly sampled from the intermediate performance group until 50% had clinical assessments and from the good performance group until 5% had clinical assessments. To determine incident cases of dementia after the baseline interview and clinical assessments, followup interviews were conducted 2 years later. As with the baseline prevalence study, these incidence interviews were performed in two phases: in-home screening followed by a full diagnostic evaluation, primarily of those with a high probability of dementia. The clinical-assessment phase in both the baseline and follow-up waves included a physician examination, cognitive testing, and an informant interview. Physicians interviewed each subject and performed physical and neurological examinations. During the interview, the physician conducted mental status assessment and reviewed history and functional competence. Laboratory and imaging studies were ordered as clinically indicated. The structured cognitive evaluation of the subjects was the Consortium to Establish a Registry for Alzheimer s Disease (CERAD) neuropsychological battery. 22 The battery of tests included the Mini-Mental State Exam (MMSE), Animal Fluency Test, Boston Naming Test, Constructional Praxis, and Word List Learning. Normative values for these tests had been obtained at each site. 23,24 Also, we conducted a structured interview with a key informant, usually a relative of the subject. The interview had four components: 1) a historical review of the subject s cognitive functioning, memory, language, judgment, and reasoning, as well as personality functioning; this review included a description of the onset and progression of any reported symptoms of cognitive decline; 2) a review of the subject s performance in the various domains of the activities of daily living; 3) a review of the subject s medical history and medication; and 4) the subject s history of dementiaassociated conditions. All patients were diagnosed at each site after a consensus diagnostic conference composed of psychiatrists, neurologists, neuropsychologists, and nurses. Data from the screening interview were not available to the clinicians and were not used to arrive at the diagnosis. Diagnosis of dementia was according to DSM-III- R 5 5 and ICD criteria, and dementia severity was coded with the Clinical Dementia Rating Scale. 26 NINCDS/ADRDA criteria 27 were used for probable and possible AD; ICD-10 criteria were used for vascular dementia and other secondary dementias. Every attempt was made to ensure diagnostic consistency across sites. The diagnostic process involved senior, experienced members of the faculties of medicine at the University of Ibadan and at Indiana University, familiar with both the criteria for dementia and with the local culture. 18,19 The site clinicians in a consensus conference first reviewed the information, and then a site diagnosis was made. Later, one or more clinicians from the other site reviewed all of the clinical data, blind to the local team s diagnosis, and recorded an independent diagnosis. Kappa agreement for between-site diagnoses was 0.8 for dementia. A consensus conference involving clinicians from both sites was held to review cases with discrepant diagnosis between sites, and then a final consensus diagnosis was made. Six questions on personality change, originating from The Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) 28,29 were administered during the second part of the screening interview. These were 1) Have you noticed any changes in his/her personality? 2) Has he/she become more irritable? 3) Has he/she become more stubborn? 4) Does he/she show less concern for other people? 5) Is there a loss of interest or enjoyment in things in general? and 6) Has he/she lost interest in things he/she used to enjoy? Personality change was defined as an affirmative answer to any of the questions. No personality change was defined as a negative answer to all of the questions. Apathy was defined as an affirmative answer to any of the last two questions. Also, there was one question asking whether the subject is more depressed than he/she used to be. Figure 1 shows the exclusion criteria and then number of people excluded by each site. To ensure that participants at follow-up did not have dementia at baseline, only subjects diagnosed as not showing dementia at baseline for all performance groups were included in the analysis. Also, subjects not diagnosed in the group with low probability of dementia were also included in the analysis. An additional 393 people from Indianapolis and 223 people from Ibadan were excluded because their diagnosis status could not be obtained at the incidence interview. Finally, 642 people were excluded from the Indianapolis cohort and 1 person from the Ibadan cohort because they had no informant interview. This resulted in a sample of 3,021 subjects with Am J Geriatr Psychiatry 10:6, November-December

4 Personality Changes and Dementia data on personality change and incident dementia status, with 2,084 subjects residing in Ibadan and 937 subjects residing in Indianapolis. Statistical Analysis We used chi-square tests for differences in proportions of personality change across sites. We used twosample t-tests for mean differences and chi-square tests for differences in proportions of demographic and functional characteristics across personality change and dementia status. Multiple logistic-regression models were used to model dementia as a function of any change in personality, adjusting for demographic and functional characteristics at baseline. RESULTS The distribution of any change in personality by site is presented in Table 1. The percentage of subjects in Ibadan with any change in personality (46.8%) was significantly higher (v 2 [1] 35.2; p 0.001) than subjects in Indianapolis (35.2%). Approximately 18% of Indianapolis subjects were reported with apathy, significantly higher (v 2 [1] 43.2; p 0.001) than the 9% reported for Ibadan subjects. The percentage of Ibadan subjects reported showing less concern for others (39.4%) was significantly higher (v 2 [1] 347.8; p ) than that reported for Indianapolis subjects (6.0%). Approximately 15% of Indianapolis subjects had reported problems with general change, significantly higher (v 2 [1] 76.8; p 0.001) than those in Ibadan (4.6%). TABLE 1. Occurrence of any change in personality, by site Ibadan (n 2,084) Indianapolis (n 937) Any change in personality 46.8% 35.2% b Specific questions: general change 4.6% 13.6% b more stubborn 3.7% 16.4% b more irritable 2.8% 16.7% b less concern for others 39.4% 6.0% b apathetic 9.4% 17.9% b a Differences between Ibadian and Indianapolis samples. b v 2 [1]. p a FIGURE 1. Criteria for inclusion in the analysis, by site Ibadan (n=2,487) Probability of Dementia Low Medium High Probability of Dementia Low Indianapolis (n=2,212) Medium High Diagnosed dementia Diagnosed no-dementia Not diagnosed 1, , Eligible for analysis 2, , n=2,487 n=1,971 n=2, missing incident diagnosis 1 missing informant: personality data n=1, missing incident diagnosis 642 missing informants: personality data n=2,084 n=937 4 Am J Geriatr Psychiatry 10:6, November-December 2002

5 Smith-Gamble et al. Approximately 15% of Indianapolis subjects were reported as being more stubborn and more irritable, whereas fewer than 5% of Ibadan subjects had reported problems of being more stubborn and more irritable. Associations of any change in personality with demographics and baseline functioning scores are presented by site in Table 2. Subjects with any change in personality had a significantly higher occurrence of disability at both Ibadan (v 2 [1] 75.7; p 0.001) and Indianapolis (v 2 [1] 32.3; p 0.001). Subjects with any change in personality in Ibadan had significantly lower baseline cognitive scores (t [1,755] 2.9; p 0.003) and significantly more functional problems (t [1,755] 16.2; p 0.001) than subjects without any change in personality. Subject in Indianapolis with change in personality also had significantly lower baseline cognitive scores (t [611] 2.9; p 0.004) and significantly more functional problems (t [448] 13.1; p 0.001) than subjects without change in personality. Change in personality was associated with gender only in Indianapolis, whereas there was no association of age or education with change in personality at either site. Overall, 45 subjects were diagnosed with dementia, 24 (19 possible or probable AD) at Indianapolis and 21 (19 possible or probable AD) at Ibadan. In the overall sample, the mean age (79.3 years; standard deviation [SD : 8.1) of dementia subjects was significantly higher (t [44.9] 6.3; p 0.001) than the mean age (71.7 years, SD: 6.6) of subjects without dementia. Subjects with dementia had a significantly higher (v 2 [1] 12.3; p 0.001) percentage of change in personality (68.9%) than subjects without dementia (42.8%). Subjects with dementia also had significantly more functional problems, lower baseline cognitive scores, and a higher occurrence of disability (data not shown). The percentage of subjects in Indianapolis with dementia (2.6%) is significantly higher (v 2 [1] 10.6; p 0.001) than in Ibadan (1.0%). Associations of dementia with demographics, baseline functioning scores, and change in personality by site are presented in Table 3. Subjects with dementia have a higher occurrence of any change in personality than subjects without dementia at both Ibadan (v 2 [1] 5.2; p 0.023) and Indianapolis (v 2 [1] 10.7; p 0.001). Consistent with the overall sample, subjects with dementia were older, had a higher percentage of physical disability, had significantly lower cognitive scores, and had significantly more functioning problems than subjects without dementia at each site. There was no association of dementia with gender or education at either site. The multiple logistic-regression model predicting dementia for the overall sample is presented in Table 4. For the overall sample, subjects in Indianapolis have 5.5 times the odds of having dementia (Wald v 2 [1] 17.4; p 0.001) as the Ibadan subjects. Increasing age and increasing functional problems are significantly associated with increased odds of dementia, whereas increasing cognitive score is significantly associated with decreased odds of dementia. Gender, education, and physical disability were not associated with dementia in this model. Even after adjustment for demographic and functional characteristics, subjects with any change in personality have 2.1 times the odds of having dementia (Wald v 2 [1] 4.0; p 0.044) as the subjects with no change in personality. TABLE 2. Univariate comparisons of demographics and functional data between subjects with and without any change in personality, by site Any Change in Personality (n 975) lbadan No Change in Personality (n 1,109) p a Any Change in Personality (n 330) Indianapolis No Change in Personality (n 607) Women, % b b Low education, % b b Disabled, % b b Mean age, years (SD) 71.5 (7.3) 71.3 (6.2) c 73.1 (6.3) 72.7 (6.5) c Mean baseline cognitive score (SD) 28.7 (3.1) 29.0 (2.2) c 30.8 (2.1) 31.2 (1.8) c Mean baseline functional problems (SD) 2.8 (2.2) 1.5 (1.3) c 3.6 (2.8) 1.4 (1.6) c Note: SD: standard deviation. a p: Value for testing differences in factors across personality change status. b v 2 [1]. c Two-sample t-test. p a Am J Geriatr Psychiatry 10:6, November-December

6 Personality Changes and Dementia TABLE 3. Univariate comparisons of demographics, functional data, and personality change between subjects with and without dementia, by site Dementia (n 21) Ibaden No Dementia Dementia (n 2,063) p a (n 24) Indianapolis No Dementia (n 913) Women, % b b Low education, % b b Disabled, % b b Any change in personality, % b b Mean age, years (SD) 79.2 (8.3) 71.3 (6.7) c 79.4 (8.1) 72.7 (6.3) c Mean baseline cognitive score (SD) 24.9 (4.6) 28.9 (2.6) c 27.4 (3.2) 31.1 (1.8) c Mean baseline functional problems (SD) 4.8 (4.3) 2.1 (1.8) c 5.2 (3.2) 2.1 (2.3) c Note: SD: standard deviation. ap: Value for testing differences in factors across dementia status. b v 2 [1]. c Two-sample t-test. p a To determine whether the association between dementia and personality change was consistent across sites, we ran multiple logistic-regression models predicting dementia for each site. Results from these two tables are presented in Table 5. Odds ratios for all variables, with the exception of physical disability are similar in magnitude across both sites and similar to those obtained for the overall sample. At each site, increasing age is significantly associated with increased odds of dementia, and increasing baseline cognitive scores are associated with decreased odds of dementia. The odds of increased dementia for people with personality change are 1.8 (Wald v 2 [1] 1.26; p 0.262) at Ibadan and 2.2 (Wald v 2 [1] 2.10; p 0.147). Although these are not significantly different, they are similar in magnitude at each site and similar to the odds ratio obtained for the overall sample. This may suggest that the nonsignificant results for change in personality are due to TABLE 4. Multiple logistic-regression results for predicting odds of dementia for the overall sample Overall Sample (n 3, 014) Odds Ratio 95% C1 p a Indianapolis 5.50 ( ) Age 1.08 ( ) Female 0.72 ( ) Low education 0.77 ( ) Disabled 0.70 ( ) Baseline cognitive score 0.80 ( ) Baseline functional score 1.14 ( ) Any change in personality 2.10 ( ) Note: CI: confidence interval. a p value is based on Wald v 2 [1]. decreased power, since the number of dementia subjects at each site was small. Eleven percent of the total sample (6.6% Indianapolis; 13.7% Ibadan) answered affirmatively to the question on depression. Approximately 24% of subjects with change in personality had informant-reported depression in Ibadan, whereas approximately 10% of subjects in Indianapolis with reported change in personality also had reported depression. After adjusting for other factors, depression was not significantly associated with dementia (Wald v 2 [1] 2.56; p 0.109). Including subjects with reported depression with those with personality change increased the odds ratio slightly, from 2.1 to 2.3. DISCUSSION In this study, change in personality as reported by informants, was a significant predictor of incident dementia and AD for the combined African American and Yoruba sample, even after adjusting for cognition and functional status. This study confirms the previous clinical reports that personality change can predate cognitive decline as an initial symptom of dementia or AD. It is particularly noteworthy that this finding was similar in two population-based studies from different sociodemographic and cultural backgrounds, the Yoruba, in Nigeria, and the African American, in Indianapolis. The timing of this change, occurring 2 years before the diagnosis of dementia, makes it likely that the personality changes represent the earlier symptoms of the disease process. There were some significant differences however, 6 Am J Geriatr Psychiatry 10:6, November-December 2002

7 Smith-Gamble et al. in the reported personality changes between the two sites. The Ibadan informants reported a greater percentage of subjects with less concern for others (39.4%) than did the Indianapolis informants (6.0%), whereas the Indianapolis informants reported more symptoms of stubbornness, irritability, and apathy. We have reported previously on similar site differences on personality change with these dementia subjects. 30 It is too early to speculate about the reasons for these differences in the two populations, but we hope that a planned, more comprehensive study in the future will allow us to explore their possible implications. Personality is generally regarded to be relatively stable throughout life In a previous paper, we stated that informant reports of changes in personality were not uncommon in nondemented elderly African Americans, occurring in approximately one-third of the subjects. These changes were not associated with increasing age, but rather with reports of poor functioning in activities of daily living and physical disability, and a history of cancer. 36 Similarly, in this analysis, changes in personality were commonly reported in nondemented Yoruba and African Americans. As in the previous paper, these were also significantly associated with physical disability and poor daily functioning. The questions in our screening interview were included primarily to gain information to satisfy the DSM-III-R criteria for dementia regarding alterations in personality. Although the questions were framed as inquiries into personality change, it is possible that what the informants were reporting were degrees of psychological distress in response to disease and infirmity, rather than fundamental alterations in personality. The concept of personality is complex, and methods of evaluation are by no means standard. Nevertheless, our study suggests that reports of personality change by informants should be considered seriously by physicians and may represent the earliest symptoms of a disease process. Depression has been reported both as an early symptom of AD and as a risk factor. Depression is frequently part of the dementia syndrome. The prevalence of depression is higher in patients with dementia than in those without dementia Depression is also a risk factor for dementia and cognitive decline. 39,40 It is possible that the personality changes reported here reflect a depressive syndrome. 39 Depressive episodes occurring premorbidly have also been associated with an increased risk of subsequent AD. 39,41 In our study, we did include a separate question inquiring about the presence of depressive symptoms. The single answer to depression was not specifically associated with increased odds of dementia but, after adjusting for other factors, did increase the additive risk when added to the other questions regarding personality change. It is unlikely, given the frequency of the changes reported by the informants, that these always represented a formal depressive syndrome. Regardless of whether or not the questions of personality change simply reflect syndromal or subsyndromal depression, results strongly suggest that clinicians should review an array of personality or behavioral alterations, in addition to asking direct questions about the presence or absence of depression. There are several limitations to this study. The numbers of incident dementia cases at each site were small (24 African Americans and 21 Yoruba). The questionnaire on personality change was derived from a clinical questionnaire and certainly did not measure all the possible nuances of personality. One possible limitation to this study is that information on personality change was obtained from informants. A study by Jacomb et al. 42 suggests that an informant s emotional state may need TABLE 5. Multiple logistic-regression results for predicting odds of dementia, by site Ibadan (n 2,083) Indianapolis (n 931) Odds Ratio 95% CI p a Odds Ratio 95% CI p a Age 1.07 ( ) ( ) Female 0.89 ( ) ( ) Low education 0.63 ( ) ( ) Disabled 0.36 ( ) ( ) Baseline cognitive score 0.83 ( ) ( ) Baseline functional score 1.13 ( ) ( ) Any change in personality 1.81 ( ) ( ) Note: CI: confidence interval. a p value is based on Wald v 2 [1]. Am J Geriatr Psychiatry 10:6, November-December

8 Personality Changes and Dementia to be taken into account when interpreting data based on informant reports. Nevertheless, the finding that in two markedly different populations, socioeconomically and culturally, personality change is a significant predictor of future dementia, independent of cognition and functional status, should make clinicians particularly sensitive to these reports when they occur in their elderly patients. 10. This work was supported by NIH Grant AG References 1. Advisory Board on Alzheimer s Disease: Alzheimer s Disease and Related Dementias: Acute and Long-Term Care Services. U.S. Dept.of Health and Human Services, Washington, DC, NIH Publication , Snow C: Medicare HMOs develop plan for future of Alzheimer s programming. 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9 Smith-Gamble et al. 35. Costa PT Jr, McCrae RR: Personality in adulthood: a six-year longitudinal study of self-report and spouse ratings on the NEO Personality Inventory. J Pers Soc Psychol 1988; 54: Gao S, Dolan N, Hall KS, et al: The association of demographic factors and physical illness with personality change in a community sample of elderly African Americans. Am J Geriatr Psychiatry 2000; 8: Forsell Y, Winblad B: Major depression in a population of demented and nondemented older people: prevalence and correlates. J Am Geriatr Soc 1998; 46: Wragg RE, Jeste DV: Overview of depression and psychosis in Alzheimer s disease. Am J Psychiatry 1989; 146: Devanand DP, Sano M, Tang MX, et al: Depressed mood and the incidence of Alzheimer s disease in the elderly living in the community. Arch Gen Psychiatry 1996; 53: Heinik J, Keren P, Vainer-Benaiah Z, et al: Agreement between spouses and children in descriptions of personality change in Alzheimer s disease. Isr J Psychiatry Relat Sci 1999; 36: Jorm AF: Is depression a risk factor for dementia or cognitive decline? a review. Gerontology 2000; 46: Jacomb PA, Jorm AF, Korten AE, et al: Factors associated with informant-rated personality problems in an elderly population. Aging and Mental Health 2000; 4:36 42 Am J Geriatr Psychiatry 10:6, November-December

10 AJGP 10:6 Author Query Smith-Gamble et al. [AuQ1] In Table 1, please confirm superscripts correct (1="a"; 2="b," etc.) There is no entry relating to the "3" or "c" legend; it was therefore omitted.