Bowel symptoms in women planning surgery for pelvic organ prolapse

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1 American Journal of Obstetrics and Gynecology (2006) 195, Bowel symptoms in women planning surgery for pelvic organ prolapse Catherine S. Bradley, MD, MSCE, a Morton B. Brown, PhD, b Geoffrey W. Cundiff, MD, c Patricia S. Goode, MD, d Kimberly S. Kenton, MD, e Ingrid E. Nygaard, MD, MS, f William E. Whitehead, PhD, g Patricia A. Wren, PhD, MPH, h Anne M. Weber, MD, MS, i for the Pelvic Floor Disorders Network y Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, a Iowa City, IA; Department of Biostatistics, b University of Michigan, Ann Arbor, MI; Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, c Baltimore, MD; Birmingham/Atlanta Geriatric Research, Education and Clinical Center, Birmingham Veterans Affairs Medical Center, and University of Alabama at Birmingham, d Birmingham, AL; Department of Obstetrics and Gynecology, Loyola University Medical Center, e Maywood, IL; Department of Obstetrics and Gynecology, University of Utah, f Salt Lake City, UT; Department of Medicine, University of North Carolina at Chapel Hill, g Chapel Hill, NC; Department of Health Behavior and Health Education, School of Public Health, h University of Michigan, Ann Arbor, MI; National Institute of Child Health and Human Development, National Institutes of Health, i Bethesda, MD Received for publication January 16, 2006; revised July 5, 2006; accepted July 10, 2006 KEY WORDS Bowel symptoms Pelvic organ prolapse Constipation Questionnaires Objective: The objective of the study was to measure associations between bowel symptoms and prolapse. Study design: Baseline data were analyzed from 322 women in the Colpopexy And Urinary Reduction Efforts trial of sacrocolpopexy with or without Burch colposuspension. Women completed the Colorectal-Anal Distress Inventory and Colorectal-Anal Impact Questionnaire and underwent Pelvic Organ Prolapse Quantification. Associations between symptoms and questionnaire scores and Pelvic Organ Prolapse Quantification measures were assessed. Results: Mean age was 61 G 10 years. Pelvic Organ Prolapse Quantification stages were II (14%), III (67%), and IV (19%). Colorectal-Anal Distress Inventory symptoms did not increase with prolapse stage. Colorectal-Anal Distress Inventory obstructive subscale scores were higher in stage II women (median 29 [interquartile range 8,92] versus 17 [0,33] and 25 [0,38] for stages III and IV, respectively; adjusted P =.01). The few statistically significant correlations between symptoms and vaginal descent were negative and weak (less than 0.2). Conclusion: Bowel symptoms and questionnaire scores do not increase with prolapse stage in women presenting for sacrocolpopexy. Ó 2006 Mosby, Inc. All rights reserved. Supported by grants from the National Institute of Child Health and Human Development (U01 HD41249, U10 HD41268, U10 HD41248, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41269, and U10 HD41267). Presented at the 32nd Annual Meeting of the Society of Gynecologic Surgeons, April 3-5, 2006, Tucson, AZ. y Members of the Pelvic Floor Disorders Network are listed in the Appendix. Reprints not available from the authors /$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi: /j.ajog

2 Bradley et al 1815 Bowel symptoms, such as constipation, straining, splinting to defecate, and anal incontinence, are common in women and often attributed to the presence of pelvic organ prolapse. However, the degree to which prolapse contributes to bowel symptoms is unclear. Fialkow et al 1 found that difficulty with evacuation of stool and the need for manual assistance with defecation were more common in women with posterior vaginal prolapse, whereas other symptoms (incomplete defecation, fecal incontinence, and bowel movement frequency) were not. Arya et al 2 found that women with prolapse had higher constipation scores on a condition-specific questionnaire and more often reported the need for manual assistance with defecation when compared with women without prolapse. Other studies reported weak or absent associations between symptoms of anorectal dysfunction and the presence or severity of prolapse. 3-8 The Colpopexy And Urinary Reduction Efforts (CARE) study, which included women without symptoms of stress incontinence and undergoing sacrocolpopexy for pelvic organ prolapse, provided the opportunity to examine whether bowel symptoms are associated with increasing vaginal descent in women undergoing surgery for their prolapse. The objective of this analysis was to measure the associations between bowel symptoms reported via validated questionnaires, with a quantified examination of pelvic organ prolapse. We hypothesized that as prolapse became more severe, the symptoms of defecating dysfunction would also become greater. Material and methods The CARE trial was performed through the Pelvic Floor Disorders Network, a cooperative agreement network sponsored by the National Institute of Child Health and Human Development. Each Pelvic Floor Disorders Network site received institutional review board approval, and all women provided written informed consent. This study included baseline data from CARE, a randomized surgical trial of 322 women with advanced prolapse and no stress incontinence symptoms who underwent sacrocolpopexy and were randomly assigned to prolapse surgery with or without Burch colposuspension. Study methods have been described and primary results reported. 9,10 At the time of enrollment, demographic and clinical information was obtained by interview. Prolapse was characterized using the Pelvic Organ Prolapse Quantification (POP-Q) system. 11 The POP-Q examinations were performed with subjects in the lithotomy position, and measurements (other than vaginal length) were taken as the subject maximally strained. Measurements of the genital hiatus (GH) and the perineal body (PB) were repeated when the subject was at rest. Validated disease-specific questionnaires administered by telephone by a Quality-of-Life Interviewing Center included the Pelvic Floor Distress Inventory and the Pelvic Floor Impact Questionnaire (PFIQ). 12,13 The Pelvic Floor Distress Inventory assesses symptom distress related to pelvic floor disorders. One of its 3 scales is the Colorectal-Anal Distress Inventory (CRADI), which includes 16 symptom items divided into 4 subscales (obstructive, incontinence, pain/irritation, and rectal prolapse). Respondents are asked whether they usually experience each symptom and if so, how much the symptom bothers them on a scale of 1 (not at all) to 4 (quite a bit). Subscale scores range from 0 to 100, with higher scores reflecting increased symptom bother. Scores from the 4 available subscales can be summed to yield a total CRADI score, ranging from 0 to 400. The PFIQ assesses the impact of pelvic floor symptoms on women s activities of daily living. The PFIQ consists of 3 scales, including the Colorectal-Anal Impact Questionnaire (CRAIQ). The 31 items related to the impact of bowel symptoms are grouped into four subscales (travel, social, emotional, and physical activity). Response options for each item range from 1 (not at all) to 4 (quite a bit). Similar to the CRADI, subscale scores range from 0 to 100; the total CRAIQ score ranges from 0 to 400. Again, higher scores indicate greater impact on daily activities or worse functioning. Yes/no responses to individual CRADI items were used to estimate the prevalence of symptoms and associations between symptoms and POP-Q stage. For correlation analyses, CRADI symptom responses were coded as ordinal variables (ranging from 0 [symptom absent] to 4 [symptom present and quite a bit bothersome]). The POP-Q points Bp, Ba, C, and the most dependent POP-Q point assessed descent of the posterior, anterior, and apical compartments and the maximum point of descent overall, respectively. Possible indicators of perineal descent were calculated from the GH and PB measurements, including change in GH (strain rest), change in PB (strain rest), and the sum of GH and PB measurements taken while straining (GH C PB). Continuous variables were summarized by mean and SD. Ordinal variables were summarized by median with interquartile range (IQR). Associations between CRADI symptoms and POP-Q stage were assessed by the c 2 test (unadjusted) or the Mantel-Haenszel odds ratio (when adjusted). The mean CRADI and CRAIQ scores were compared between POP-Q stages by a Kruskal-Wallis test (unadjusted) or a general linear model F test (when adjusted). Adjusted analyses controlled for clinically relevant variables: age (younger than 65 and 65 years or older); body mass index (BMI) (less than 30, 30 to less than 35, and 35 kg/m 2 or greater), parity (0, 1, 2-3, and 4 or greater); and prior posterior repair.

3 1816 Bradley et al Age and BMI were categorized as above when computing the Mantel-Haenszel statistic and were treated as continuous when fitting the general linear model. The Spearman and Pearson correlation coefficients were used to estimate the associations between individual symptom severity and the CRADI or CRAIQ scores, respectively, and POP-Q measures. Statistical significance was reported with P value of.05 or less. No adjustments were made for multiple comparisons. With more than 300 subjects, there is 80% power to identify a correlation of 0.16 using a 2-tailed 5% level of significance. Also, with sample sizes based on the CARE POP-Q distribution, there is 80% power to identify a change of 0.65 SD between means or approximately 30% between proportions. Results The subjects were 322 women with age 61 G 10 years. Parity was 3 (IQR 2, 4), BMI was 27 G 5 kg/m 2,and 93% were Caucasian. Surgical history included 226 (70%) with prior hysterectomy, 126 (39%) with prolapse surgery, and 71 (22%) with prior posterior repair. Subjects POP-Q results were 14% (n = 44) with stage II, 67% (n = 217) with stage III, and 19% (n = 61) with stage IV. The median posterior POP-Q point (Bp) was at the hymen (0 cm [IQR 2, C4 cm]), and the median point of maximum descent of any vaginal compartment was 3.5 cm beyond the hymen (IQR C2, C5 cm). Age, smoking, and prior surgery for prolapse differed by prolapse stage. Women with stage II prolapse were younger (mean age 56 years versus 61 and 66 years for stages III and IV, respectively; P!.0001), more likely to be current smokers (16% versus 5% and 9% for stages III and IV, respectively; P =.042), and to have had prior surgery (57% versus 36% and 37% for stages III and IV, respectively; P =.036). The difference in proportions reporting previous posterior repair (37%, 30%, and 20% for stages II, III, and IV, respectively) was not statistically significant (P =.21). Eight women did not complete the questionnaires and could not be included in the analyses. Six symptoms from the obstructive and pain/irritation subscales were significantly more common in women with stage II prolapse who reported at least moderate bother (3 or 4), including digital assistance in defecating (P =.0067), straining (P =.0094), feeling of incomplete defecation (P =.0039), abdominal pain prior to bowel movements (P =.0024), lower back pain (P =.0057), and pain with defecation (P =.016) (Table I). However, after adjustments for age, BMI, parity, and prior posterior repair, these P values were nonsignificant; differences in BMI and prior posterior repair between prolapse stages reduced the significance of the unadjusted tests. Other symptoms (both overall symptom prevalence and symptoms associated with at least moderate bother) did not increase with prolapse stage. CRADI and CRAIQ scores by stage are presented in Table II. CRADI obstructive scores were higher in women with stages II and IV prolapse (P =.015), indicating increased symptom bother (Figure). CRAIQ emotional and physical activity scores were higher in women with stage II prolapse (P =.016 and.014, respectively), reflecting more impact on daily activities related to their bowel symptoms. The association between the CRADI obstructive subscale score and prolapse stage remained significant (P =.0084) in the adjusted analyses. Associations between bowel symptoms and prolapse were also not seen when analyzed by individual POP-Q measurements, rather than by stage. Vaginal descent, measured in centimeters of the posterior, anterior, or apical vagina, or the leading edge of prolapse overall correlated poorly with the CRADI symptoms and CRADI and CRAIQ summary and subscale scores. The few statistically significant correlations between vaginal descent and symptoms were negative (inversely associated) and weak (all less than 0.2). The correlations were re-examined among women with more severe prolapse (that is, stages III and IV), and the results did not change. Again, no correlations greater than 0.2 were noted. For instance, correlations between the CRADI summary and CRADI obstructive subscale scores and point Bp in women with stages III and IV prolapse were each only 0.15 (although statistically significant with P =.014 and.015, respectively). Correlations between GH and PB measures and bowel symptoms and scores were also very weak (all less than 0.2). Of these, the highest correlations were between anal incontinence with urgency and GHCPB (r = 0.16, P =.0043), the CRADI incontinence score and GHCPB (r = 0.15, P =.0099), and the CRAIQ social score and PB (strain) (r = 0.19, P =.0010). Similar results were obtained when these correlations were reexamined after excluding women with stage II prolapse. Comment Although bowel symptoms are common in women with stages II-IV prolapse presenting for sacrocolpopexy, these symptoms do not increase as prolapse increases. In fact, in unadjusted analyses, women with stage II prolapse reported more obstructive and pain-related bowel symptoms than women with stages III and IV prolapse; but most of these differences were not significant when adjusted for clinical factors, suggesting that other factors may explain the increased symptoms. Perhaps women with stage II prolapse who present for sacrocolpopexy do so because of related symptoms

4 Bradley et al 1817 Table I Individual CRADI symptoms (overall symptom prevalence and those reporting each symptom with at least moderate bother) (n [%]) in women by POP-Q stage POP-Q stage Symptom Total (n = 314) II (n = 43) III (n = 211) IV (n = 60) Digital assistance 89 (28) 19 (44) 53 (25) 17 (28) At least moderately bothered 62 (20) 16 (37) 34 (16) 12 (20) Strain 113 (36) 23 (54) 72 (34) 18 (30) At least moderately bothered 86 (27) 20 (47) 50 (24) 16 (27) Incomplete defecation 139 (45) 25 (60) 88 (42) 26 (43) At least moderately bothered 80 (26) 19 (45) 44 (21) 17 (28) Anal incontinence, with activity 77 (25) 10 (23) 56 (27) 11 (18) At least moderately bothered 47 (15) 7 (16) 32 (15) 8 (13) Anal incontinence, with urgency 68 (22) 9 (21) 46 (22) 13 (22) At least moderately bothered 41 (13) 7 (16) 27 (13) 7 (12) Anal incontinence, with formed stool 14 (4) 3 (7) 8 (4) 3 (5) At least moderately bothered 12 (4) 3 (7) 6 (3) 3 (5) Anal incontinence, with loose stool 61 (19) 10 (23) 38 (18) 13 (22) At least moderately bothered 48 (15) 8 (19) 31 (15) 9 (15) Anal incontinence, with gas 117 (37) 17 (40) 74 (35) 26 (43) At least moderately bothered 78 (25) 13 (30) 45 (21) 20 (33) Lower back pain 137 (44) 24 (56) 86 (41) 27 (46) At least moderately bothered 107 (34) 24 (56) 65 (31) 18 (31) Abdominal pain prior to defecation 58 (18) 13 (30) 40 (19) 5 (8) At least moderately bothered 34 (11) 10 (23) 23 (11) 1 (2) Pain with defecation 25 (8) 8 (19) 12 (6) 5 (8) At least moderately bothered 16 (5) 6 (14) 7 (3) 3 (5) Fecal urgency 82 (26) 12 (28) 52 (25) 18 (30) At least moderately bothered 39 (12) 6 (14) 25 (12) 8 (13) Mucus with defecation 44 (14) 11 (26) 26 (12) 7 (12) At least moderately bothered 15 (5) 4 (9) 9 (4) 2 (3) Hemorrhoids 120 (38) 18 (42) 83 (39) 19 (32) At least moderately bothered 46 (15) 8 (19) 32 (15) 6 (10) Pain with straining 85 (27) 14 (33) 57 (27) 14 (23) At least moderately bothered 58 (19) 11 (27) 42 (20) 5 (8) Rectal prolapse 45 (14) 4 (10) 29 (14) 12 (20) At least moderately bothered 29 (9) 2 (5) 20 (10) 7 (12) Table II The CRADI and CRAIQ subscale and summary scores (median [IQR]) in women by POP-Q stage POP-Q stage Questionnaire (possible score range) II (n = 43) III (n = 211) IV (n = 60) CRADI (0-400) 58 (33-129) 46 (14-104) 48 (22-94) CRADI-obstructive (0-100)* 29 (8-92) 17 (0-33) 25 (0-38) CRADI-incontinence (0-100) 0 (0-35) 5 (0-25) 10 (0-30) CRADI-pain/irritation (0-100) 14 (4-50) 11 (4-25) 14 (4-21) CRAIQ (0-400) 13 (0-80) 4 (0-31) 8 (0-36) CRAIQ-travel (0-100) 0 (0-20) 0 (0-8) 0 (0-8) CRAIQ-social (0-100) 0 (0-13) 0 (0-2) 0 (0-5) CRAIQ-emotional (0-100) 13 (0-25) 0 (0-7) 0 (0-7) CRAIQ-physical activity (0-100) 4 (0-25) 0 (0-13) 0 (0-15) * P =.01 (general linear model F test; adjusted for age, BMI, parity, and prior posterior repair). rather than prolapse severity. Still, even after excluding women with stage II prolapse, symptoms remained only weakly associated with prolapse in women with stages III and IV prolapse. The weak correlations identified between vaginal descent and the CRADI symptoms and scores suggest that prolapse alone (as measured by the POP-Q) cannot explain the presence or absence of bowel symptoms.

5 1818 Bradley et al Figure The CRADI obstructive subscale score in women by POP-Q stage. Median score and IQR are represented with squares and vertical lines, respectively. P value =.01 (general linear model F test; adjusted for age, BMI, parity, and prior posterior repair). We examined the relationship between prolapse stage and bowel function using a validated symptom questionnaire. Using nonvalidated measures completed by urogynecology patients, other investigators also found no 3 or minimal 5 associations between prolapse and bowel symptoms. A large database study including more than 1900 urology and urogynecology patients found a similar weak correlation between digital assistance to defecate and POP-Q point Bp (r = 0.23). 7 Other studies that included women with the full range of prolapse stages also described a lack of associations between bowel symptoms and prolapse stage. 4,6,8 In contrast, some investigators have reported positive associations between bowel complaints and prolapse. In 185 urogynecology and urology patients, splinting and the sense that the stool comes to the rectum but will not come out were more common in women with stage II or greater posterior prolapse, compared with those with less than stage II posterior prolapse. 1 However, important clinical differences existed between the groups (the prolapse group was older, more often postmenopausal, and more likely to have had hysterectomy), which may have influenced the results. A recent case-control study compared women with prolapse (Baden-Walker stage 2 or greater) with controls and found that prolapse patients were more likely to have constipation (adjusted odds ratio 2.9, 95% confidence interval ). 2 On the other hand, among the women with prolapse, constipation symptom severity did not differ by prolapse stage. Given the lack of standardized symptom questions and variable populations, it is difficult to compare rates of symptoms in CARE to previous studies. However, our reported rates of obstructive bowel symptoms appear similar to those reported in other studies of women presenting for urogynecologic care. Twenty-eight percent of women in our study reported yes to the question, Do you usually have to push on the vagina or around the rectum to have or complete a bowel movement? In similar populations, 16% to 38% of women answer yes to similar questions. 1,3-5,7 Few studies address bowel symptoms in women not presenting for treatment of a pelvic floor disorder. One study using a modified version of the CRADI in older women found 20% reported digital assistance to defecate more than once in 3 months. 14 A large national survey found that 25% of women aged 60 years and older used digital assistance to have a bowel movement, and 16% of all women met symptom criteria for constipation. 15 The high rate of bowel symptoms in women without evident pelvic floor disorders further suggests that bowel symptoms may not be directly related to prolapse. This study has several strengths. It was prospective, and our aims and statistical plan were designed before data analysis. We used validated questionnaires and a quantitative, reproducible prolapse examination. We also acknowledge potential limitations. We did not include women without prolapse or women with prolapse not seeking surgical treatment; therefore, our results may not be generalizable to other populations. We tested numerous associations and did not correct for multiple analyses. Some of these associations may have occurred by chance and should be re-examined in future studies. Lastly, this was a cross-sectional analysis, and we do not know whether symptoms developed before or after prolapse or whether symptoms will improve or deteriorate after surgery. Future study of bowel symptoms in the CARE population after surgery may help address this important clinical issue. Acknowledgment The authors thank Dr. Robert Park, the Chair of the Pelvic Floor Disorders Network Steering Committee, for his contributions to the network. References 1. Fialkow MF, Gardella C, Melville J, Lentz GM, Fenner DE. Posterior vaginal wall defects and their relation to measures of pelvic floor neuromuscular function and posterior compartment symptoms. Am J Obstet Gynecol 2002;187: Arya LA, Novi JM, Shaunik A, Morgan MA, Bradley CS. Pelvic organ prolapse, constipation, and dietary fiber intake in women: a case-control study. Am J Obstet Gynecol 2005;192: Burrows LJ, Meyn LA, Walters MD, Weber AM. Pelvic symptoms in women with pelvic organ prolapse. Obstet Gynecol 2004;104:

6 Bradley et al Weber AM, Walters MD, Ballard LA, Booher DL, Piedmonte MR. Posterior vaginal prolapse and bowel function. Am J Obstet Gynecol 1998;179: Ellerkmann RM, Cundiff GW, Melick CF, Nihira MA, Leffler K, Bent AE. Correlation of symptoms with location and severity of pelvic organ prolapse. Am J Obstet Gynecol 2001;185: Klingele CJ, Bharucha AE, Fletcher JG, Gebhart JB, Riederer SG, Zinsmeister AR. Pelvic organ prolapse in defecatory disorders. Obstet Gynecol 2005;106: Tan JS, Lukacz ES, Menefee SA, Powell CR, Nager CW. Predictive value of prolapse symptoms: a large database study. Int Urogynecol J Pelvic Floor Dysfunct 2005;16: Kahn MA, Breitkopf CR, Valley MT, Woodman PJ, O Boyle AL, Bland DI, et al. Pelvic Organ Support Study (POSST) and bowel symptoms: straining at stool is associated with perineal and anterior vaginal descent in a general gynecologic population. Am J Obstet Gynecol 2005;192: Brubaker L, Cundiff G, Fine P, Nygaard I, Richter H, Visco A, et al. A randomized trial of colpopexy and urinary reduction efforts (CARE): design and methods. Control Clin Trials 2003;24: Brubaker L, Cundiff GW, Fine P, Nygaard I, Richter HE, Visco AG, et al. Abdominal sacrocolpopexy with Burch colposuspension to reduce urinary stress incontinence. N Engl J Med 2006;354: Bump RC, Mattiasson A, Bo K, Brubaker LP, DeLancey JO, Klarskov P, et al. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol 1996;175: Barber MD, Kuchibhatla MN, Pieper CF, Bump RC. Psychometric evaluation of 2 comprehensive condition-specific quality of life instruments for women with pelvic floor disorders. Am J Obstet Gynecol 2001;185: Wren PA, Janz NK, Brubaker L, Fitzgerald MP, Weber AM, LaPorte FB, et al. Reliability of health-related quality-of-life measures 1 year after surgical procedures for pelvic floor disorders. Am J Obstet Gynecol 2005;192: Bradley CS, Kennedy CM, Nygaard IE. Pelvic floor symptoms and lifestyle factors in older women. J Womens Health 2005;14: Stewart WF, Liberman JN, Sandler RS, Woods MS, Stemhagen A, Chee E, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999;94: Appendix Pelvic Floor Disorders Network Members University of Alabama at Birmingham: Holly E. Richter, PhD, MD, Principal Investigator, Kathryn Burgio, PhD, Patricia Goode, MD, Mark Lockhart, MD, R. Edward Varner, MD, Velria Willis, RN, BSN; Baylor College of Medicine: Paul M. Fine, MD, Principal Investigator, Naomi Frierson, Peter M. Lotze, MD, Peter K. Thompson, MD; University of Iowa: Ingrid Nygaard, MD, MS, Principal Investigator, Catherine Bradley, MD, MSCE, Debra Brandt, RN, Denise Haury, RN, Karl Kreder, MD, Satish Rao, MD; Johns Hopkins Medical Institutes: Geoffrey Cundiff, MD, Principal Investigator, Victoria Handa, MD, Mary Elizabeth Sauter, NP, Jamie Wright, MD; Loyola University, Chicago: Linda Brubaker, MD, MS, Principal Investigator, Charity Ball, RN, MaryPat FitzGerald, MD, Kimberly Kenton, MD, Dorothea Koch, RN; University of Michigan: Morton B. Brown, PhD, Principal Investigator, Yang Wang Casher, MS, John O. L. DeLancey, MD, James Imus, MS, Nancy K. Janz, PhD, Beverly Marchant, RN, BS, Dean G. Smith, PhD, John T. Wei, MD, MS, Patricia A. Wren, PhD; University of North Carolina at Chapel Hill: Anthony G. Visco, MD, Principal Investigator, AnnaMarie Connolly, MD, Mary L. Jannelli, MD, John Lavelle, MD, Mary J. Loomis, RN, Anita K. Murphy, NP, Ellen C. Wells, MD, William Whitehead, PhD; University of Pittsburgh/Magee-Womens Hospitals: Halina Zyczynski, MD, Principal Investigator, Diane Borello-France, PhD, Judy A. Gruss, BS, MS, Wendy Leng, MD, Pamela A. Moalli, MD, PhD; Steering Committee Chairman: Robert Park, MD; National Institutes of Health Project Scientist: Anne M. Weber, MD, MS.