PEDIATRICS Vol. 118 No. 6 December 2006, pp. 2280-2289 (doi:10.1542/peds.2006-1946)
ARTICLE |
A National Survey of Pediatrician Knowledge and Attitudes Regarding Human Papillomavirus Vaccination
a Departments of Pediatrics
e Preventive Medicine and Biometrics
g Family Medicine
b Colorado Health Outcomes Program, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
c Childrens Outcomes Research Program, Childrens Hospital, Denver, Colorado
d Division of Sexually Transmitted Diseases Prevention
f National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
| ABSTRACT |
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OBJECTIVE. A human papillomavirus vaccine was licensed in June 2006. The vaccine is quadrivalent, protecting against 2 human papillomavirus strains that cause cervical cancer and 2 that cause genital warts. The objective of this study was to determine physician characteristics, knowledge, and attitudes associated with an intention to recommend human papillomavirus vaccination.
METHODS. Between August and October 2005, a cross-sectional survey was administered to a national network of 431 pediatricians. The network was developed from a random sample of American Academy of Pediatrics members and was designed to be representative of the organizations membership with respect to urban/rural location, practice type, and region. The survey was conducted before human papillomavirus vaccine licensure and therefore focused on a candidate quadrivalent human papillomavirus vaccine and a range of potential vaccination recommendations. The main outcome measure was intention to recommend a quadrivalent human papillomavirus vaccine to young adolescent (10- to 12-year-old) females.
RESULTS. Survey response rate was 68%. If endorsed by national health organizations, 46% of respondents would recommend vaccination for 10- to 12-year-old females, 77% for 13- to 15-year-old females, and 89% for 16- to 18-year-old females. Corresponding rates for males were 37%, 67%, and 82%, respectively. Whereas 60% of respondents thought that parents would be concerned that human papillomavirus vaccination may encourage risky sexual behaviors, 11% reported that they themselves had this concern. Respondents who believed that other new adolescent immunization recommendations (eg, meningococcal, pertussis) would facilitate human papillomavirus vaccine implementation were more likely to intend to recommend vaccination.
CONCLUSIONS. Although a national sample of pediatricians expressed a high level of acceptance of human papillomavirus vaccination in older adolescent females, fewer than one half anticipated giving human papillomavirus vaccine to younger female patients. Provider concerns about parental vaccine acceptance will need to be addressed to optimize human papillomavirus vaccination implementation.
Key Words: immunization human papillomavirus vaccine physician attitudes
Abbreviations: HPVhuman papillomavirus FDAFood and Drug Administration ACIPAdvisory Committee on Immunization Practices VFCVaccines for Children AAPAmerican Academy of Pediatrics
An estimated 20 million people in the United States are currently infected with genital human papillomavirus (HPV), and roughly 6.2 million people will acquire a new genital HPV infection each year.1,2 The incidence of HPV is highest among sexually active adolescent girls and young adult women, with a cumulative incidence of 30% to 50% reported in females who were 15 to 23 years of age and followed for 2 to 3 years.35 Of the many HPV types that infect the human genital tract, certain types (types 16, 18, and many others) are designated as high risk because of their association with cervical and other anogenital cancers, whereas low-risk types (eg, types 6 and 11) are associated with genital warts.6 Persistent infection with oncogenic HPV types is a necessary but not sufficient cause of virtually all cervical cancers, with HPV DNA detected in 99.7% of cervical cancers.7 Although the incidence of and death rates for cervical cancer in the United States have declined in recent decades, largely as a result of Papanicolaou screening during routine pelvic examinations, an estimated 10400 new cases of invasive cervical cancer occurred in 2005, with 3700 deaths from the disease.8 The economic burden that is associated with the treatment of preinvasive cancerous lesions and the follow-up of false-positive Papanicolaou tests also is substantial.9 In men, HPV infections can cause genital warts or lead to penile or anal cancer, although at rates well below the rates of cervical cancer in women.10
HPV vaccination has the potential to reduce greatly the morbidity and the mortality that are associated with genital HPV infections. Several HPV vaccines have been developed, including a bivalent (types 16 and 18)11,12 and a quadrivalent (types 6, 11, 16, and 18) vaccine.13 HPV types 16 and 18 cause
70% of cervical cancer worldwide,14 whereas types 6 and 11 are responsible for an estimated 90% of anogenital warts.15 In a randomized, placebo-controlled trial of a quadrivalent vaccine, persistent HPV infection or HPV-associated genital disease was reduced 90% among vaccine recipients during a 36-month follow-up period.13 In an investigation that was published recently in abstract form, quadrivalent HPV vaccine was found to have 97% efficacy at preventing HPV 16/18-related grade 2 or 3 cervical intraepithelial neoplasia, adenocarcinoma in situ, and cervical cancer.16 On June 8, 2006, a quadrivalent HPV vaccine was licensed by the Food and Drug Administration (FDA) for use in females who are 9 to 26 years of age.17 On June 29, 2006, the Advisory Committee on Immunization Practices (ACIP) voted to recommend routine HPV immunization of 11- to 12-year-old females, although these recommendations are not considered official until published in the Morbidity and Mortality Weekly Report.18
After a new vaccine is approved by the FDA and recommended for use by the ACIP and other national health organizations, vaccination implementation begins, a process that can encounter numerous challenges. As was seen with the pneumococcal conjugate vaccine that was licensed in 2000, new vaccine use may be hampered by high purchase costs, inadequate reimbursement, incomplete coverage of the vaccine by private insurers, differences in the timing of vaccine availability between private and public sources (eg, the federal Vaccines for Children [VFC] program), and vaccine demand outstripping supply.1922 HPV vaccination efforts may face additional barriers,23 because the vaccine targets a sexually transmitted infection; the nature and the consequences of HPV infection are poorly understood by the public24,25; and, unlike several other vaccines that currently are recommended for adolescents,26 HPV vaccine will require 3 doses.
Pediatricians will have an important role in promoting HPV vaccination, given that young adolescents are more likely to be seen by pediatricians than any other providers27 and that providers are known to have substantial influence on their patients immunization decisions.28,29 Successful immunization delivery may be facilitated by knowledge about pediatrician attitudes regarding HPV vaccination, particularly if this information is available before the development of educational messages and materials for providers and the public. The current study, undertaken before the licensure of an HPV vaccine, had the following objectives: (1) to assess the knowledge and the attitudes of a nationally representative sample of pediatricians regarding HPV vaccination and (2) to determine the physician characteristics, knowledge, and attitudes that are associated with an intention to recommend HPV vaccination for 10- to 12-year-old female patients.
| METHODS |
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From August to October 2005, a survey was conducted regarding HPV infection and vaccination in a national sample of pediatricians. This study was reviewed by the human subjects review board at the University of Colorado at Denver and Health Sciences Center, approved as exempt research, and informed consent was not required.
Population
The investigation was undertaken as part of the Vaccine Policy Collaborative Initiative, a program for conducting rapid-response physician surveys that was developed collaboratively with the Centers for Disease Control and Prevention. In early 2005, a national network of primary care pediatricians was developed for the purposes of this survey program. Power calculations established that 300 completed surveys would yield 80% power with a 5% type I error rate to detect a 16% difference when comparing dichotomous variables between 2 groups of equal size. Assuming a 75% survey response rate, the network therefore was designed to have
400 participants.
For development of the network, up to 4 recruitment letters, approved by the American Academy of Pediatrics (AAP) and printed on AAP letterhead, were mailed or e-mailed to a random sample of 2500 AAP members. Pediatricians were asked whether they would be willing to respond to 2 to 4 immunization-related surveys per year. Respondents who spent <50% of their time delivering primary care were excluded. No incentives to participate were provided.
This "sentinel" pediatrician network was designed to be representative of the AAP membership overall. Using data from the AAP periodic membership survey,30 we determined the overall distribution of AAP members with respect to 3 characteristics: region of the country (Northwest, South, Midwest, and West), practice location (urban inner city, urban noninner city/suburban, and rural), and practice setting (private, managed care, and community/hospital based). Thirty-six unique combinations of practice characteristics were possible, each with an expected frequency based on the AAP membership survey. Applying these frequencies to a targeted sample size of 400, we then determined the expected number of respondents for each of these 36 "cells." For cells with an excess number of respondents (>110% of the expected frequency), eligible physicians were randomly allocated for study participation. For cells with an inadequate number of respondents (<90% expected), 1 additional recruitment attempt was made. In this manner, a sentinel network of 431 pediatricians was developed, with 29 (81%) of 36 cells containing the expected number of physicians and a range of 1 to 3 fewer physicians than expected per cell among the 7 underrepresented cells.
Survey Design
The survey instrument focused on the following conceptual areas: attitudes about adolescent patients and sexuality, knowledge about HPV infections, attitudes about HPV vaccination, and perceived barriers to HPV vaccination. The survey was pilot-tested in a community advisory panel, a group of 6 practicing pediatricians from different regions of the country. After answering questions about their HPV-related knowledge, respondents were given a brief paragraph about a quadrivalent HPV vaccine.13 Respondents then were asked, if this particular vaccine were FDA-approved and recommended for routine use, how likely they would be to vaccinate female and male patients in 3 age groups: 10- to 12-year-olds, 13- to 15-year-olds, and 16- to 18-year-olds. The survey focused on a quadrivalent HPV vaccine because, at the time the survey instrument was developed, it was anticipated that this vaccine would be the first HPV vaccine licensed in the United States. When the survey was developed, it was not known that 11- to 12-year-old females would be the initial group targeted for routine HPV vaccination.18
Survey Administration
When recruited for the sentinel network, pediatricians were asked their preference regarding whether to be surveyed by Internet or mail. All 280 pediatricians who preferred responding by Internet or did not have a preference were surveyed via the Internet; the remaining 151 were surveyed by mail. The Internet survey was administered through a Web-based product (Zoomerang; MarketTools Inc, Mill Valley, CA), whereas the mail survey was sent via standard mail. The Internet group received up to 9 reminders via e-mail to complete the survey, whereas the mail group received up to 3 surveys in the mail. For both groups, responses were accepted for 6 weeks after the first survey was sent.
Outcome Measures
The primary outcome measure was intention to recommend a quadrivalent HPV vaccine for 10- to 12-year-old female patients. Secondary outcome measures were vaccination intentions regarding male adolescents and older female adolescents.
Analytical Methods
Items regarding physician attitudes were asked using 4-point Likert scales,31 with responses collapsed into dichotomous variables for analyses. Six individual knowledge items were collapsed into an HPV knowledge scale (number correct/number answered). Multivariate analyses were performed to test the hypothesized relationship between pediatricians HPV-related attitudes and their intentions regarding HPV vaccination, while controlling for other potential factors that influence intentions, such as physician gender. For these analyses, the primary outcome was treated as a dichotomous variable (very/somewhat likely to give HPV vaccine versus very/somewhat unlikely or not sure). Internet and mail surveys were pooled together for all analyses, given that physician attitudes generally have been found to be comparable when obtained by either method.32 All statistical analyses were performed using SAS 8.0 (SAS Institute, Inc, Cary, NC).
| RESULTS |
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Survey Response and Characteristics of Respondents
Of the 431 participants in the sentinel pediatrician network, 294 (68%) returned completed surveys, with a 71% response rate among those surveyed by Internet compared with a 62% rate in those surveyed by mail (P = .051). As presented in Table 1, survey respondents and nonrespondents were similar with respect to age, gender, practice location, region of the country, and practice setting. No additional information was available for survey nonrespondents. Several additional characteristics of respondents practices also are shown in Table 1.
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Adolescent Patients and Sexuality
Overall, 88% of pediatricians reported feeling comfortable discussing issues of sexuality with female adolescents, compared with 93% with male adolescents. Responses varied by physician gender; however, 97% of female versus 81% of male pediatricians reported feeling comfortable discussing sexuality with female patients (P < .001), whereas 91% of female versus 95% of male pediatricians were comfortable addressing sexuality with male patients (P = .20). Sixty-four percent of all respondents did not routinely perform gynecologic examinations, and 49% did not routinely provide prescriptions for oral contraceptives in their practice. Whereas 92% reported regularly inquiring about sexual activity at health maintenance visits, fewer (66%) reported that they usually were aware when adolescent patients had become sexually active. Finally, respondents were asked what proportions of their 13- to 15-year-old patients were sexually active; 36% reported 0% to 9%, 35% reported 10% to 19%, and 29% reported 20% or more.
Knowledge About HPV
Responses to several true/false questions regarding HPV are presented in Table 2. Pediatricians HPV-related knowledge varied, with 98% aware that HPV causes genital warts in males and females but almost one third unaware that HPV has a causative role in virtually all cervical cancers. Before being given an informational paragraph about a prospective quadrivalent HPV vaccine, 43% of pediatricians did not know that highly effective HPV vaccines were currently under development.
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Intention to Recommend HPV Vaccination
Pediatricians intentions regarding recommending a quadrivalent HPV vaccine for female and male patients in various age groups are illustrated in Fig 1. Respondents were more likely to recommend HPV vaccination to older compared with younger adolescents (Cochran-Armitage test for trend: females, P < .0001; males, P < .0001). Within each age group, respondents were more likely to recommend vaccine to female versus male patients (McNemars test for paired data: P < .0001 for the comparison within each age group).
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Thirty (10%) respondents reported being unlikely to recommend HPV vaccination to any patients of any age. Compared with the 264 respondents who would recommend HPV vaccine to 1 or more patient groups, these 30 "nonadopters" were more likely to be male (74% male among nonadopters versus 51% male among adopters; P = .02), to feel uncomfortable discussing issues of sexuality with female patients (22% vs 10%; P = .05), and not to prescribe routinely oral contraceptives in their practices (68% vs 47%; P = .03).
Attitudes About HPV Vaccination
Table 3 presents respondent attitudes regarding HPV vaccination. Whereas 60% of respondents thought that parents would be concerned that HPV vaccination might encourage risky sexual behaviors, 11% reported that they themselves had this concern. Sixty-four percent thought that other new adolescent immunization recommendations (eg, meningococcal, pertussis) would make it easier to introduce HPV vaccine in their practice. Also shown in Table 3, a number of attitudes about HPV vaccination were associated in bivariate analyses with likelihood of giving HPV vaccine to 10- to 12-year-old females.
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In addition, respondents were asked how they anticipated discussing HPV vaccination with families. With female patients and their parents, pediatricians anticipated strongly emphasizing prevention of cervical cancer in the patient herself (86% of respondents), the safety of the vaccine (72%), vaccine efficacy (71%), and prevention of genital warts in the patient herself (60%). With male patients/parents, pediatricians expected to highlight vaccine safety (71%), vaccine efficacy (69%), prevention of genital warts in the patient himself (68%), and prevention of cervical cancer in female sexual partners (62%).
Perceived Barriers to Vaccination
Seventy-seven percent of pediatricians reported that the lack of adequate reimbursement would definitely/somewhat be a barrier to vaccination, and 51% thought that the "up-front" costs of HPV vaccine for their practice also would be a barrier. In addition, 57% thought that parental vaccine refusals would be a barrier for female patients and 64% for male patients.
Factors Associated With Intention to Vaccinate
As shown in Table 4, factors that were positively associated in multivariate analyses with being likely to vaccinate 10- to 12-year-old female patients were knowledge that effective HPV vaccines were under development and belief that other new adolescent vaccination recommendations would facilitate introducing HPV vaccine. Factors that were negatively associated with intention to vaccinate young female adolescents included considering it necessary to discuss sexuality before vaccination, thinking that parents would be upset if a vaccine against a sexually transmitted infection were offered to young adolescents, and belief that parents refusing vaccination would be a barrier.
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Separate multivariate analyses were performed to determine factors that were associated with intending to vaccinate 10- to 12-year-old male patients. Results generally were similar to those described in the previous paragraph regarding female patients, with providers concerned about parental reactions to vaccination against a sexually transmitted infection less likely to intend to vaccinate (data not shown). However, female physicians were more likely than male physicians to anticipate vaccinating young male adolescents (odds ratio: 2.03; 95% confidence interval: 1.173.50), a factor that was not associated with the intention to vaccinate female patients.
| DISCUSSION |
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HPV vaccines have great potential to reduce the morbidity and the mortality that are associated with HPV infections, with the first HPV vaccine recently licensed by the FDA17 and other vaccines under development.11,12 In a national survey of pediatricians, conducted before HPV vaccine licensure, we found a high degree of overall acceptance for the use of an HPV vaccine that is directed against cervical cancer and genital warts. Eighty-nine percent of surveyed pediatricians intended to use a quadrivalent HPV vaccine for at least some groups of adolescents, although respondents were more likely to foresee vaccinating older rather than younger adolescents and female rather than male patients. In fact, only 46% of respondents anticipated giving HPV vaccine to 10- to 12-year-old females, and some respondents were concerned about parents negative reactions to the idea of vaccinating young adolescents against a sexually transmitted infection. These findings should be examined in the context of recently issued provisional ACIP recommendations for HPV prevention: HPV vaccine is recommended for routine use in 11- to 12-year-old females, "catch-up" vaccination of 13- to 26-year-old females is recommended, the vaccine ideally should be given before the onset of sexual activity, and females who are already sexually active also should be vaccinated.18
The findings from this and other studies of HPV vaccine acceptance have important implications for the implementation of HPV vaccination recommendations. Almost three quarters of surveyed pediatricians thought that parents would be upset that a vaccine against a sexually transmitted vaccine was offered to young adolescents, and similar concerns have been expressed in previous surveys of physicians regarding HPV vaccination.33,34 However, these apprehensions may not be entirely warranted, given that focus groups and surveys that have been conducted with parents of adolescents have found most parents likely to be accepting of vaccines against sexually transmitted infections.3539 When recommending HPV vaccine to female patients, pediatricians anticipated emphasizing cervical cancer prevention more strongly than other vaccine aspects, a clear message that may mitigate concerns about parental vaccine acceptance. Nonetheless, it will be helpful for national health organizations to develop for providers educational materials that offer guidance about how to discuss HPV vaccination with parents and patients. Guidelines for providers regarding how to handle parental refusals of HPV vaccine also may be helpful. Because parents who initially refuse a vaccine against a sexually transmitted infection may consider vaccinating the child at an older age,40 providers will need a system (eg, patient reminder/recall) for contacting families who have refused or otherwise missed HPV vaccination, recognizing that reminder/recall can be less effective in adolescents compared with other patient populations.41,42
Although a minority of surveyed pediatricians believed that HPV vaccination inadvertently could promote risky sexual behavior among vaccinated patients, many respondents anticipated this concern among their patients parents. Indeed, research indicates that some parental opposition to HPV vaccination is linked to this belief, and similar concerns have appeared in the news media.36,43,44 Although it is impossible currently to evaluate whether those who are vaccinated against HPV will participate in more risky behavior, other adolescent research suggests against it. Namely, this concern is based on the assumption that fear of HPV infection is a motivation for safer sex or abstinence. However, previous research indicated very limited knowledge about HPV among adolescents,24 and nationally representative data indicate that fear of sexually transmitted infections (including HIV) is not a major motivation for abstinence among young people.45 There also is no evidence of increased sexual risk among adolescents with the introduction of interventions such as school-based condom availability programs and emergency contraception.46,47 Finally, multiple other factors are associated with adolescent sexual behavior including parental,48,49 school,50,51 and community influence,52 and adolescents decisions about whether to have sexual intercourse rarely are based on a single factor such as fear of HPV infection.
In the current investigation, roughly one half the number of pediatricians would recommend HPV vaccination for 10- to 12-year-old females as would recommend vaccination for 16- to 18-year-olds. A similar disinclination regarding vaccinating younger adolescents against HPV or other sexually transmitted infections has been found in previous surveys of pediatricians,33 family physicians,34 gynecologists,53 and nurse practitioners.54 Therefore, we anticipate that providers will need clear educational messages about the importance of completing HPV vaccination during young adolescence. Although it will be compelling to link HPV vaccination with other vaccines that are recommended routinely for 11- to 12-year-olds (eg, tetanus-diphtheria-acellular pertussis vaccine and, depending on vaccine supplies, meningococcal vaccine),26 providers will need to understand that the timing of HPV vaccination in early adolescence is not merely a matter of convenience but may be critically important to overall vaccine effectiveness. HPV vaccination may not be effective if given after a persistent HPV infection has already developed,13 the incidence of HPV is known to rise rapidly after sexual initiation,5 and roughly 6% of 13-year-old as well as 58% of 17-year-old females have ever had sexual intercourse.45
It is unclear what the role of male vaccination will be in future HPV vaccination programs. A cervical cancer/genital warts vaccine should reduce the burden of genital warts in vaccinated males and in theory also may reduce the transmission of oncogenic HPV types from vaccinated males to unvaccinated females.10,55 However, no data are available regarding the efficacy of male vaccination as a means of reducing HPV burden in females. In addition, estimates of the cost-effectiveness of male vaccination vary widely depending on assumptions about vaccine coverage rates, vaccine efficacy, and HPV transmission characteristics.56,57 Because the recently licensed quadrivalent HPV vaccine was approved for use in females only,17 any vaccination in males would be considered an "off-label" use. If, in the future, this or other HPV vaccines are FDA approved for use in both genders, then data from the current investigation suggest that pediatricians generally would be accepting of vaccine use in male patients.
Finally, given the high prevalence of provider concerns about vaccine cost and reimbursement issues documented in this and other investigations,33,34 addressing these financial concerns will be a challenging but important aspect of HPV vaccination implementation. After the introduction of pneumococcal conjugate vaccine in 2000, data from pediatricians and family physicians suggest that an initial lack of insurance reimbursement led providers to delay vaccination for some or all of their patients.21,22 In addition, the timing of vaccine coverage by private plans compared with coverage by the federal VFC program may have led to a 2-tiered system in which privately insured children received vaccine in their medical home, whereas Medicaid-insured and uninsured children were referred to public health clinics for vaccination.21 However difficult it may be to actualize, consideration should be given to coordinating VFC approval of HPV vaccine, the incorporation of HPV vaccine into the coverage plans of major insurers, and the issuance of official HPV vaccination recommendations by national health organizations.
This investigation is subject to several limitations. Only the views of pediatricians were assessed, although other specialties, such as family medicine and obstetrics/gynecology, also will have important roles in national HPV vaccination programs. Although the sentinel physician network that was used for this study was designed to be representative of the AAP membership overall, it is possible that the attitudes of sentinel physicians differed in some way from US pediatricians in general. Although this study had a relatively high survey response rate, it is not known whether nonrespondents held different views about HPV vaccination than did survey respondents. In addition, the study was not powered to explore how HPV-related attitudes may differ between smaller subgroups of pediatricians, such as those who care predominantly for publicly insured patients; therefore, the results may not generalize to pediatricians who work in all types of settings. Because an HPV vaccine was not available for routine use at the time this survey was administered, we measured intention to give HPV vaccine rather than actual immunization behaviors. Finally, we assessed pediatrician attitudes about the newly licensed quadrivalent HPV vaccine; it is possible that attitudes about other prospective HPV vaccines would differ from the views documented in this study.
| CONCLUSION |
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In a national survey of pediatricians, we found a high level of acceptance overall for HPV vaccination, particularly in older female adolescents. However, fewer than one half anticipated giving a quadrivalent HPV vaccine to young female adolescents, the primary group that will be targeted for routine HPV vaccination. Provider attitudes may change in response to the recent licensure of an HPV vaccine and the issuance of provisional guidelines for its use. However, data from the present investigation suggest that provider concerns about parental vaccine acceptance and reimbursement issues will need to be addressed to ensure optimal implementation of new HPV vaccination recommendations.
| ACKNOWLEDGMENTS |
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This investigation was funded by the Centers for Disease Control and Prevention. This funding was obtained and administered through the Rocky Mountain Prevention Research Center, University of Colorado at Denver and Health Sciences Center.
We acknowledge the contributions of Lynn M. Olson, PhD, and Karen OConnor of the American Academy of Pediatrics for assistance in establishing the pediatric sentinel physician network. We also thank Jennifer Pyrzanowski for assistance with manuscript preparation. Finally, we thank the sentinel physicians for time and effort in responding to this survey.
| FOOTNOTES |
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Accepted Aug 24, 2006.
Address correspondence to Matthew F. Daley, MD, 1056 E 19th Ave, B032, Denver, CO 80218. E-mail: daley.matthew{at}tchden.org
Portions of this work were presented at the meeting of the Advisory Committee on Immunization Practices; October 2627, 2005; Atlanta, GA; the 40th National Immunization Conference; March 69, 2006; Atlanta, GA; and the annual meeting of the Pediatric Academic Societies; April 29May 2, 2006; San Francisco, CA.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Dr Daley had full access to all of the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis
The authors have indicated they have no financial relationships relevant to this article to disclose.
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