Dr Cauley has received research support from Merck & Company, Eli Lilly & Company, Pfizer Pharmaceuticals, and Novartis Pharmaceuticals. She has also received consulting fees from Eli Lilly & Company and Novartis Pharmaceuticals. She is on the speaker's bureau for Merck and Company. All other authors state they have no conflicts of interest.
To identify risk factors for fractures in multi-ethnic women, we studied 159,579 women enrolled in the Women's Health Initiative. In general, risk factors for fractures were similar across ethnic groups. However, irrespective of their ethnicity, women with multiple risk factors have a high risk of fracture. Targeting these high-risk women for screening and intervention could reduce fractures.
Introduction: Fracture rates tend to be lower in minority women, but consequences may be greater. In addition, the number of fractures is expected to increase in minority women because of current demographic trends. There are limited prospective data on risk factors for fractures in minority women.
Materials and Methods: We studied 159,579 women 50–79 yr of age enrolled in the Women's Health Initiative. Information on risk factors was obtained by questionnaire or examination. Nonspine fractures that occurred after study entry were identified over an average follow-up of 8 ± 2.6 (SD) yr.
Results: Annualized rates (%) of fracture in whites, blacks, Hispanics, Asians, and American Indians were 2.0, 0.9, 1.3, 1.2, and 2.0, respectively. Significant predictors [HR (95% CI)] of fractures by ethnic group were as follows: blacks: at least a high school education, 1.22 (1.0, 1.5); (+) fracture history, 1.7 (1.4, 2.2); and more than two falls, 1.7 (1.9, 2.0); Hispanics: height (>162 cm), 1.6 (1.1, 2.2); (+) fracture history, 1.9 (1.4, 2.5); more than two falls, 1.8 (1.4, 2.3); arthritis, 1.3 (1.1, 1.6); corticosteroid use, 3.9 (1.9, 8.0); and parental history of fracture, 1.3 (1.0, 1.6); Asians: age (per 5 yr), 1.2 (1.0, 1.3); (+) fracture history, 1.5 (1.1, 2.0); current hormone therapy (HT), 0.7 (0.5, 0.8); parity (at least five), 1.8 (1.1, 3.0); more than two falls, 1.4 (1.1, 1.9); American Indian: (+) fracture history, 2. 9 (1.5, 5.7); current HT, 0.5 (0.3, 0.9). Women with eight or more risk factors had more than a 2-fold higher rate of fracture compared with women with four or fewer risk factors. Two ethnicity × risk factor interactions were identified: age and fall history.
Conclusions: Irrespective of their ethnicity, women with multiple risk factors have a high risk of fracture. Targeting these high-risk women for screening and intervention could reduce fractures.
Osteoporosis is a major public health problem, that over a lifetime results in fractures in 40% of aging women.(1) Although the lifetime risk of fractures is lower in nonwhite women,(2–4) it is still substantial and may be rising. Whereas the incidence of hip fracture declined in white women, it doubled among Hispanic women from 1983 to 2000.(5) The consequences of osteoporotic fractures may be greater among nonwhite women. Mortality after a hip fracture is higher among black than white women.(6) Black women who suffer a hip fracture have longer hospitalization stays and are more likely to be nonambulatory compared with white women.(7) Mexican Americans who reported a previous hip fracture were four times as likely to be disabled.(8)
The Surgeon General's Report on Bone Health and Osteoporosis noted the lack of information on ethnic and racial minorities as a priority.(9) Many risk factors have been identified in prospective studies of white women.(10) There are few prospective studies of risk factors for fracture among minority women. The objective of this study was to identify risk factors for fracture in a multiethnic cohort of women enrolled in the Women's Health Initiative (WHI). A second objective was to test the hypothesis that ethnic differences in fracture rates were, in part, mediated by ethnic differences in risk factors.
MATERIALS AND METHODS
The WHI is composed of an observational study (OS, n = 92,368) and three overlapping clinical trials (CT, n = 67,211) of hormone therapy (HT), dietary modification, and calcium and vitamin D supplementation. Women were recruited from 1993 to 1998. Women were eligible if they were 50–79 yr of age and postmenopausal. Study methods have been described in detail elsewhere.(11) All participants signed informed consent forms that were approved by institutional review boards. Follow-up ranged from 0 to 12.4 yr for a mean of 8.0 ± 2.6 (SD) yr.
Assessment of risk factors
Information on race or ethnicity was obtained by self-report and included “whites” (not of Hispanic origin); “blacks” (not of Hispanic origin); “Hispanics/Latinos” (Mexican, Cuban, Puerto Rican, Central American, or South American); “Asians or Pacific Islanders” (Chinese, Indo-Chinese, Korean, Japanese, Pacific Islander, Vietnamese); “American Indian” (including Alaskan Native), or “other.” We excluded women who reported “other” race (n = 2,229) from this report. Data were collected on education, living arrangements, fracture, reproductive and medical history, alcohol intake, cigarette smoking, physical activity, general health status, diet, falls, and medications. A woman was considered depressed based on her score on the Centers for the Epidemiologic Study of Depression (CES-D) test(12) or reported use of antidepressants. Body mass index was calculated as weight in kilograms divided by height in square meters.
If a woman had been randomly assigned to the estrogen and progestin (E + P) or the E-alone group or reported use of E + P or E alone at baseline, she was considered a current hormone user. Women randomly assigned to placebo and women who reported past or never use at baseline were considered never/past users.
BMD at the total hip and posterior-anterior spine was measured in 12,705 women (97% of women enrolled in Pittsburgh, PA; Birmingham, AL; and Phoenix/Tucson, AZ) with DXA (Hologic, Waltham, MA, USA). BMD models were confined to white, black, and Hispanic women because of insufficient numbers of Asians and American Indians with BMD. Standard protocols for positioning and analysis were used by technicians who were trained and certified.
Follow-up and fracture ascertainment
At study end, 5.7% of participants were deceased, and 4.3% of participants had withdrawn or were lost to follow-up. The primary outcome of the study included all fractures that occurred after study entry except for those of the fingers, toes, face, skull, or sternum. Local and central review of radiology reports confirmed all hip fractures. Information on other fractures was confirmed by radiographic report among CT women. For women in the OS, we relied on self-report of nonhip fractures. In the WHI, 80% of self-reported nonhip fractures were confirmed by physician review of medical records, suggesting that the self-report of such fractures is reasonably accurate.(13)
All analyses were performed using SAS 9.1 (Cary, NC, USA). The baseline characteristics of the women were compared across ethnicity using ANOVA and χ2 tests. We used Cox regression models that were stratified according to age at WHI baseline and WHI CT participation. The first confirmed fracture that occurred over follow-up was used in the analysis. We calculated the HRs and 95% CIs. Variables included in the final main effect model were chosen based on statistical significance (p < 0.25 in the age-adjusted univariate model), their clinical importance, and previous literature. The cut-off used to distinguish the unit of reference in the multivariable models for height, weight, and caffeine intake was the 75th percentile in the total population. We also examined the HR per 1 SD increase, and results were essentially unchanged (data not shown). For BMD, we calculated the HR for fracture per 1 SD decrease in BMD.
We examined two-way interactions using likelihood ratio tests to test whether a particular risk factor modified the risk for fracture by ethnic group. To select the most parsimonious model, we used the likelihood ratio test to compare a model that included all ethnicity-related two-way interactions to a model containing only significant two-way interactions. We calculated the number of risk factors for each individual based on the variables entered into the final multivariable model. The annualized rate of fracture was compared for women with no more than four, five to seven, and at least eight clinical risk factors.
To test whether the clinical risk factors account for ethnic differences in fracture, we calculated the HR of fracture compared with white women by ethnicity in age and multivariable adjusted models. In the subgroup of women with BMD, we calculated the HR for fracture for black and Hispanic women compared with white women in age and multivariable models and further adjusted for BMD. All p values are two-sided.
The mean age of the cohort ranged from 60.2 yr in Hispanic women to 63.6 yr among white women (Tables 1 and 2). Although the absolute differences in these characteristics across ethnicity were relatively small, in many cases, they were statistically significant because of the large sample size. The mean weight and BMD were greatest among black women and lowest among Asian or white women. In general, calcium intake was high, exceeding 1000 mg/d. Physical activity was greatest in whites and Asians and lowest in blacks. The percent with a college degree or higher was greatest among Asians and whites and lowest among Hispanics and American Indians. Less than 10% reported current smoking. Diabetes was more common among blacks and American Indians, whereas hypertension was more common among blacks. Use of postmenopausal hormones was relatively high at entry into WHI. Conversely, use of bisphosphonate and selective estrogen receptor modulators (SERMS) was low (<3%). In the subgroup with BMD, lumbar spine BMD was highest in black women and lowest in Hispanic women. Total hip BMD was also highest in black women and lowest in white and Asian women.
Table Table 1.. Baseline Characteristics of Women in WHI by Ethnicity: Continuous Variables (Mean ± SD)
Table Table 2.. Baseline Characteristics of Women in WHI by Ethnicity: Categorical Variables
Over an average 8.0 yr of follow-up, incident fractures occurred in 23,270 women, including 21,083 (15.8%) white women; 1112 (7.6%) black women; 580 (8.9%) Hispanic women; 391 (9.3%) Asian women; and 164 (14.6%) American Indian women. The annualized (%) rate of fracture was 2.0, 0.9, 1.3, 1.2, and 2.0, respectively. Hip fractures accounted for 7% of all fractures, and clinical spine fractures accounted for 9%. In the BMD subcohort of 12,705 women, fractures occurred in 1828 (18.5%) white women; 164 (9.7%) black women; and 96 (10.8%) Hispanic women, with an annualized (%) rate of fracture 2.5, 1.3, and 1.5, respectively.
The HR for fracture per 5-yr increase in age among white, black, Hispanic, Asian, and American Indian women was 1.10, 1.00, 1.10, 1.14, and 1.08, respectively (p for interaction = 0.02). There was a stepwise increase in fractures rates with age in all groups except black women (Fig. 1). Among black women, fractures rates were stable until 75+ yr of age.
Age-adjusted risk factors for fracture
Among white women, most variables were statistically significant, although the magnitude of several of these associations was weak (Table 3). The focus of the manuscript is on minority women. Risk factors that showed a significant age-adjusted association with fracture in black women included greater height, greater education, personal and parental fracture history, history of diabetes, myocardial infarction (MI), arthritis, use of nonsteroidal anti-inflammatory drugs (NSAIDs), use of corticosteroids for >2 yr, sedatives/anxiolytics, and falls. Among Hispanic women, greater education, personal and family history of fracture, history of diabetes, MI, arthritis, use of corticosteroids >2 yr, and falls were associated with a significant increase risk of fracture. Among Asian women, risk factors included personal history of fracture, depression, and falls. Use of hormones for ≥5 yr, prior oophorectomy, and excellent to good health status were each associated with a 26–36% decreased risk of fracture in Asian women. Similarly, among American-Indian women, personal and parental history of fracture, diabetes, depression, and falls were each associated with a 70–120% significant increased risk of fracture. However, both current cigarette smoking and use of corticosteroids were associated with an increased risk of fracture, but neither was significant, perhaps reflecting low statistical power.
Table Table 3.. Age-Adjusted Univariate HRs (95% CI) for Fractures Across Ethnicity
A 1 SD decrease in hip BMD was associated with a 24–46% significant increase in the risk of fracture. The association between spine BMD and subsequent fracture was weaker in all ethnic groups.
Multivariable models of risk factors for fracture
Among white women, all of the risk factors were statistically significant, although the magnitude of several associations was quite small, and they are unlikely to be of clinical significance (Table 4). Among black women, higher education, positive fracture history, and history of more than two falls were independently associated with a 20–74% significant increase in the risk of fracture. Among Hispanic women, older age, greater height, personal and family history of fracture, more than two falls, corticosteroid use (>2 yr), and history of arthritis were independently associated with an increased risk of fracture. The association with corticosteroid use was quite high, indicating an almost 4-fold increased risk of fracture. Among Asian women, older age, positive fracture history, more than two falls, and parity were independently associated with a 15–65% increased fracture risk, and current use of hormones (≥5 yr) was associated with a 37% decrease of risk of fracture. Among American-Indian women, a positive fracture history was associated with an almost 3-fold increased risk of fracture. Higher education, parental history of fracture, fall history, use of corticosteroids, and depression suggested an increased risk of fracture, but the results were not significant.
Table Table 4.. Multivariate Models of Fracture Risk: HR (95% CIs) Within Ethnic Groups
We found a significant interaction with fall history and race-ethnicity. The HR for more than two falls in white, black, Hispanic, Asian, and American-Indian women was 1.27, 1.66, 1.29, 1.37, and 1.63, respectively (p for interaction = 0.003). The risk of fracture was higher among women who reported more than two falls, but this risk was especially elevated in black and American-Indian women.
The rate of fracture increased with increasing number of risk factors (Fig. 2). The absolute rate of fracture was 2-fold higher in women with eight or more risk factors compared with women with four or fewer risk factors. Ethnic differences in fracture were attenuated among women with eight or more risk factors, especially comparing whites, Hispanics, and Asians.
The risk of fracture among black women, compared with white women, was 49% lower, even after adjusting for multiple variables (Table 5). Similarly, among Hispanic and Asian women, there was little attenuation in the HR for fracture after adjusting for multiple risk factors. In the subgroup of women with BMD, the lower risk of fracture among black and Hispanic women was independent of BMD. There was, however, some attenuation in ethnic differences in models with total hip BMD.
Table Table 5.. HR (95% CI) for Fracture Within Each Ethnic Group: White Women Form the Referent Group
This study is one of the largest longitudinal cohort studies to evaluate risk factors for fracture in a multi-ethnic cohort of older women. No previous study has recruited sufficient numbers of minority women with standardized data collection of information on a large number of risk factors for fractures and followed them for 8 yr for the incidence of fractures. Results showed that risk factors for fracture were similar across ethnic group and similar to previous reports of white women.(10) Of importance, however, women with multiple risk factors have an especially high risk of fracture, irrespective of their ethnicity. Identifying clinical risk factors that predict fracture and targeting these high-risk women for screening and intervention could reduce their fracture burden.
The annualized rate of fracture was greatest in white and American-Indian women and lowest in black women. The patterns of fracture across ethnic groups were consistent with previous studies of hip fracture.(14) The National Osteoporosis Risk Assessment (NORA) reported higher rates of fracture in Hispanic women; in WHI, fracture rates were similar in Hispanic and Asian women.(15) Few studies have reported fracture rates among American-Indian women, but American Indians in NORA also had high odds of osteoporosis.(15)
Previous history of fracture was associated with a >50% increased risk of subsequent fracture in all women. Use of corticosteroids for >2 yr was also associated with a substantial increase in fracture risk. Current use of hormone therapy was associated with lower risk of fracture in whites, Asians, and American Indians. Failure to observe an association in black and Hispanic women may have reflected the lower proportion of black and Hispanic women who used hormones for ≥5 yr. Data from the WHI hormone trials do not support a race × hormone therapy interaction.(16,17)
Previously, alcohol consumption of at least seven drinks per week was associated with a 4-fold increased risk of hip fracture in black women(18) and was linked with hip fracture in an older Japanese cohort.(19) Our analysis did not show an association between alcohol consumption and fracture in any ethnic group, perhaps reflecting the low intake among WHI minority women.
Thinness has previously been associated with an increased risk of fracture in black women.(20,21) Our results do not show a strong relationship between body weight or thinness and subsequent risk of fracture in any ethnic group. Our results are consistent with data showing that low body weight is strongly linked with hip, pelvic, and rib fractures but not to all fractures.(22) We examined body weight using the 25th percentile (<62 kg) and an absolute cut-off of BMI (<20 kg/m2). WHI women tended to be overweight or obese, with >80% of women having a BMI >25.0 kg/m2. We had too few women who were considered thin (BMI <20 kg/m2: <2%).
History of stroke has been linked to increased risk of hip fracture in black,(20) Mexican-American,(23) and Asian women.(24) In age-adjusted models, history of stroke was associated with a 40–60% increased risk of fracture in all groups except American Indians, but it was not consistently statistically significant, perhaps reflecting lower power. In age-adjusted models, self-report of diabetes was associated with a 35–100% increased risk of fracture in all groups except Asians. This is consistent with previous studies showing a higher risk of fracture among diabetics in white,(25) black,(25) and Hispanic women.(26) The prevalence of diabetes was particularly high among the American-Indian and black women, suggesting that the attributable risk for fracture associated with diabetes may be substantial in these groups. However, neither history of stroke nor diabetes was independently associated with fracture in the multivariable models. The increased risks associated with these co-morbidities may have been explained by other factors in the model. Depression has been linked to fractures in white women,(27) but we found no significant association in other ethnic groups, although the point estimates were consistent with an increased risk, especially among American-Indian women.
Higher education was associated with a greater risk of fracture, especially among black women. Previous studies have not consistently reported a socioeconomic (SES) gradient for fractures.(10) Greater parity was associated with an increased risk of fracture among Asian women, but there was no clear pattern of association in other ethnic groups. Previous analyses in white women have shown a 9% lower risk of hip fracture with each additional birth.(28) Calcium intake was not related to fracture, perhaps because intakes were high in WHI women, and there were few women who had intakes <400 mg. Our results are consistent with the overall findings from the calcium/vitamin D clinical trial, which showed no overall effect on all fractures.(29)
Use of central nervous system active medications such as sedatives and hypnotics was associated with an increased risk of fractures in age-adjusted models in black and white women, consistent with previous reports.(30) This observation was not significant in the multivariable models, perhaps reflecting the relatively low prevalence of use in our population.(30) Several medications have previously been linked with osteoporosis, including thiazide diuretics,(31) NSAIDs,(32) β-blockers,(33) and thyroid supplements.(34) However, we found no consistent association with fractures.
We observed a significant interaction between age and ethnicity, where the risk of fracture increased in a stepwise fashion with age in all groups except black women. In black women, an increased risk of fracture was not observed until the oldest age group. This is consistent with observed patterns with hip fracture, where rates exponentially increase after age 80 in black women.(35) We also observed a significant interaction with fall history and ethnicity. Although the risk of fracture was high in all women with more than two falls, the HR was significantly greater for black and American-Indian women, perhaps reflecting greater 25-hydroxy vitamin D [25(OH)D] deficiency. In prior studies, the prevalence of 25(OH)D deficiency was three times higher in blacks than in whites,(36,37) and low 25(OH)D levels have been linked to higher rates of falling.(38) Given the high prevalence of 25(OH)D deficiency(39) and the availability of inexpensive supplements, there is a need to further our understanding of vitamin D, falls, and fractures in minority women.
Despite the universal decline in BMD with age(40) and the increased risk of fracture with age,(14) preventive and therapeutic efforts focus primarily on white and Asian women. Black women with a positive fracture history were 60% less likely to receive a BMD measurement in comparison with white women.(41) A retrospective review of medical records at Howard University Hospital showed that only 9% of black women who presented with a low-impact fracture received a diagnosis of osteoporosis, and of these, only 19% were discharged on osteoporosis medication.(42) Key to prevention of fractures is the need to identify subjects at high risk. We have shown that, in every ethnic group, there is a stepwise increase in fractures with increasing number of risk factors. Information on these risk factors can easily be obtained in routine clinical settings and could help clinicians target minority women at highest risk.
Absolute risk models have recently been developed and have shown that clinical risk factors enhance the performance of BMD in the prediction of fractures.(43) In particular, for other osteoporotic fractures, excluding hip fractures, the gradients of risk for clinical risk factors alone was similar to that provided by BMD and was markedly increased by their combination. Thus, use of clinical risk factors is important for identifying women at risk for fractures. The cohorts used to develop these models were primarily white women. Many of the same clinical risk factors in these absolute risk models were similarly related to fractures in minority women in our study, including prior and parental history of fracture, and corticosteroid use.
Low BMD was related to an increased risk of fracture in black and Hispanic women. The strength of the association between BMD and nonspine fracture was similar to that observed for white women.(44) Total hip BMD was a somewhat better predictor of fracture than spine BMD in white and Hispanic women, similar to observations in other cohorts.(44) Ethnic differences in fracture were attenuated in models with hip BMD, suggesting that at least part of the differences in fracture can be explained by BMD. Nevertheless, they remained significantly different, consistent with previous studies.(15,45) Other measures of skeletal strength such as structural and material properties and hip geometry could contribute to these ethnic differences, but we had no information on these measures. The heritability of fractures is estimated to be 53%,(46) and it is likely that genetic differences contribute to ethnic differences in fracture risk.
Strengths to our study include the prospective design, inclusion of a large, racially diverse sample of well-characterized women, examination of a comprehensive range of risk factors, and longitudinal follow-up >8 yr. We focused on fractures, the most important clinical consequence of osteoporosis. Most previous studies of ethnic differences have included a single ethnic group and studied intermediate endpoints such as BMD.
There are, however, several limitations. We were unable to examine hip fractures directly because there were too few hip fractures. Nevertheless, resource use for other fractures is substantial.(47) Race/ethnicity designation was based on self-report and represents a crude surrogate for biological, environmental, cultural, and behavioral differences among individuals. Race categories may be misleading because individuals with heterogeneous ancestries are grouped together. The sample size of white women was large, and many associations were statistically significant but not necessarily clinically meaningful. Only 3 of the 40 clinical centers in WHI measured BMD, and thus we were unable to examine BMD in the whole population. Finally, WHI women were volunteers and not representative of the general U.S. population.
In conclusion, fracture rates vary across ethnic group, but risk factors for fracture were generally similar within each ethnic group. Women with the multiple risk factors have a substantially high rate of fracture, irrespective of their ethnicity. Identification of high-risk women through risk factor information may decrease the fracture risk burden.
The sponsor (NHLBI) has played a role in design and analyses of WHI. LieLing Wu is independent of any commercial funder, and she had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of the data analysis. We also thank the WHI Investigators. Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD, USA) Barbara Alving, Jacques Rossouw, Linda Pottern; Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles L Kooperberg, Ruth E Patterson, Anne McTiernan, (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker, (Medical Research Labs, Highland Heights, KY, USA) Evan Stein, (University of California at San Francisco, San Francisco, CA, USA) Steven Cummings; Clinical Centers: (Albert Einstein College of Medicine, Bronx, NY, USA) Sylvia Wassertheil-Smoller, (Baylor College of Medicine, Houston, TX, USA) Jennifer Hays, (Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA) JoAnn Manson, (Brown University, Providence, RI, USA) Annlouise R Assaf, (Emory University, Atlanta, GA, USA) Lawrence Phillips, (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) Shirley Beresford, (George Washington University Medical Center, Washington, DC, USA) Judith Hsia, (Harbor-UCLA Research and Education Institute, Torrance, CA, USA) Rowan Chlebowski, (Kaiser Permanente Center for Health Research, Portland, OR, USA) Evelyn Whitlock, (Kaiser Permanente Division of Research, Oakland, CA, USA) Bette Caan, (Medical College of Wisconsin, Milwaukee, WI, USA) Jane Morley Kotchen, (MedStar Research Institute/Howard University, Washington, DC, USA) Barbara V Howard, (Northwestern University, Chicago/Evanston, IL, USA) Linda Van Horn, (Rush-Presbyterian St Luke's Medical Center, Chicago, IL, USA) Henry Black, (Stanford Prevention Research Center, Stanford, CA, USA) Marcia L Stefanick, (State University of New York at Stony Brook, Stony Brook, NY, USA) Dorothy Lane, (The Ohio State University, Columbus, OH, USA) Rebecca Jackson, (University of Alabama at Birmingham, Birmingham, AL, USA) Cora E Lewis, (University of Arizona, Tucson/Phoenix, AZ, USA) Tamsen Bassford, (University at Buffalo, Buffalo, NY, USA) Jean Wactawski-Wende, (University of California at Davis, Sacramento, CA, USA) John Robbins, (University of California at Irvine, Orange, CA, USA) Allan Hubbell, (University of California at Los Angeles, Los Angeles, CA, USA) Howard Judd, (University of California at San Diego, LaJolla/Chula Vista, CA, USA) Robert D Langer, (University of Cincinnati, Cincinnati, OH, USA) Margery Gass, (University of Florida, Gainesville/Jacksonville, FL, USA) Marian Limacher, (University of Hawaii, Honolulu, HI, USA) David Curb, (University of Iowa, Iowa City/Davenport, IA, USA) Robert Wallace, (University of Massachusetts/Fallon Clinic, Worcester, MA, USA) Judith Ockene, (University of Medicine and Dentistry of New Jersey, Newark, NJ, USA) Norman Lasser, (University of Miami, Miami, FL, USA) Mary Jo O'Sullivan, (University of Minnesota, Minneapolis, MN, USA) Karen Margolis, (University of Nevada, Reno, NV, USA) Robert Brunner, (University of North Carolina, Chapel Hill, NC, USA) Gerardo Heiss, (University of Pittsburgh, Pittsburgh, PA, USA) Lewis Kuller, (University of Tennessee, Memphis, TN, USA) Karen C Johnson, (University of Texas Health Science Center, San Antonio, TX, USA) Robert Brzyski, (University of Wisconsin, Madison, WI, USA) Gloria E Sarto, (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Denise Bonds, and (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI, USA) Susan Hendrix.