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Formation and Current Results of a Patient-Organized Registry for ₁-Antitrypsin Deficiency*

James K. Stoller, MD, FCCP; Mark Brantly, MD; Lora E. Fleming, MD, PhD, MPH, MSc; Judy A. Bean, PhD and John Walsh for the Alpha One Foundation Research
Network Registry Investigators

A complete list of investigators is located in the ^Appendix.

Correspondence to: James K. Stoller, MD, FCCP, Department of Pulmonary and Critical Care Medicine, A 90, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: stollej{at}ccf.org

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Background: Significant challenges exist to investigating uncommon illnesses because too few patients are seen at any single clinical center to permit appropriate research studies. Recognizing this impediment to clinical research in ₁-antitrypsin deficiency, the Alpha One Foundation, a patient-organized research foundation, has collaborated with clinician-scientists to organize a voluntary registry of individuals with ₁-antitrypsin deficiency.

Purpose: To facilitate clinical research in ₁-antitrypsin deficiency by organizing a registry of affected individuals willing to be approached to participate in clinical studies.

Methods: Elements of the Alpha One Foundation Research Network Registry include a Medical and Scientific Advisory Committee, composed of physician-investigators and patient advocates, designated clinical resource centers at medical institutions with expertise in the management of individuals with ₁-antitrypsin deficiency, and a data coordinating center with responsibility for database management and analysis. Questionnaires requesting information about demographic features, ₁-antitrypsin phenotype, smoking history, and health-care utilization were distributed to prospective registrants through the following channels: mailings from the Alpha One Foundation; mailings from the clinical resource centers; and distribution by home-care and pharmaceutical companies. Information from this questionnaire formed the basis of the initial registry database.

Results: Between May 1997 and June 1999, 7,789 forms were distributed, and forms were returned by 712 unique registrants. Registrants have the following characteristics: mean (± SD) age, 49.3 ± 13.2 years; women, 47.7%; white, 96.2%; PI*ZZ phenotype, 70.7%; ex-smokers, 73.3%; COPD patients, 87.2% (emphysema patients, 54.2%; chronic bronchitis patients, 33%); and self-reported liver disease, 6.4%. The mean number of physician visits reported by registrants in the preceding 12 months was 7.8 ± 9.4, 59% reported currently receiving IV augmentation therapy, and 35% reported using supplemental oxygen at home. Examples of ongoing research studies using this unique database include: (1) a case-control study to evaluate occupational risk factors for obstructive lung disease in individuals with ₁-antitrypsin deficiency and (2) a study to evaluate the health-care costs for affected individuals.

Conclusions: A registry currently including 712 individuals with ₁-antitrypsin deficiency has been organized through a collaboration between physician-investigators and a patient-organized research foundation. Use of the registry has already facilitated studies that were previously difficult because of the paucity of identifiable study subjects. The registry cohort promises to provide an important resource for future clinical and epidemiologic studies.

Key Words: ₁-antitrypsin deficiency • emphysema • patient-organized • registry

	Introduction

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B ecause significant challenges exist to organizing studies of uncommon illnesses, novel strategies to facilitate rigorously designed research are needed. As an example of one such illness, ₁-antitrypsin deficiency¹ (prevalence, 1 in 2,800 to 5,000 live births)^{2 3 4} has received increasing attention in descriptive studies, but randomized trials of new and existing therapies have been difficult because such trials had been deemed statistically infeasible.^{1 4} At the same time, several of the following emerging factors have generated new enthusiasm for randomized controlled trials in ₁-antitrypsin deficiency:

1. Analysis of longitudinal lung function measurements from large observational studies suggests lower variability in rates of decline of lung function than once thought,¹ rendering newer and more favorable power requirements than originally estimated⁵ ;
   
2. New treatments are available that require rigorous study in order to meet US Food and Drug Administration criteria for approval; and
   
3. Patient advocacy groups (ie, the Alpha One Foundation and Alpha 1 Association) with the mission to facilitate research, patient education, and support have emerged and have grown.
   

In the context of these recent developments regarding ₁-antitrypsin deficiency, one of the novel strategies to facilitate high-quality research has been the organization of a research registry of affected individuals by the Alpha One Foundation, an organization with a mission to foster research regarding ₁-antitrypsin deficiency. The goal of this Alpha One Foundation Research Network Registry (RNR) is to identify and characterize a large cohort of ₁-antitrypsin-deficient individuals who express a willingness to be approached regarding participation in forthcoming studies, including randomized controlled trials. The current report presents the origin and goals of this RNR and describes the first 712 registrants.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
The RNR was launched in September 1997 under the direction of a medical and scientific advisory committee (MASAC) that was composed of interested voluntary, health-care professionals and patient advocates (see "Appendix"). Other components of the RNR are a group of 50 clinical centers with demonstrated expertise in the management of patients with ₁-antitrypsin deficiency, many of which had participated in the National Heart, Lung, and Blood Institute (NHLBI) Registry of Individuals with ₁-Antitrypsin Deficiency^{6 7} and the Data Coordinating Center at the University of Miami School of Medicine.

The initial questionnaire and consent form used for enrollment in the registry were drafted by the MASAC. This questionnaire addressed demographic features, characteristics of the respondent’s ₁-antitrypsin deficiency, lung function, medication use, and health-care utilization . Once finalized after several iterations, this first questionnaire and an accompanying consent form underwent review by a bioethicist. The Investigational Review Board of the University of Miami School of Medicine then formally reviewed the RNR and the proposed materials and established guidelines for conducting it. Specifically, the Data Coordinating Center was approved to collect and gather data from questionnaires developed by the MASAC.

After the registry was established and its activities had received the requisite approvals, the initial registry questionnaire was sent to prospective registry participants. Several of the following distribution sources were used: (1) direct mailing from the Alpha One Foundation to known supporters; (2) inclusion in the Alpha 1-News (the official newsletter of the Alpha 1 Association); (3) distribution to the Alpha 1 Association mailing list; (4) distribution by home-care, infusion, and pharmaceutical companies; and (5) distribution by principal investigators at the designated clinical resource centers.

Recipients were invited to complete the questionnaire and to return it for inclusion in the RNR database, which was established and maintained with confidentiality safeguards at the Data Coordinating Center. After review and approval by the MASAC of specific research protocols to which registrants were invited, letters of invitation and informed consent documents were sent to registry participants.

When principal investigators applied to the MASAC to initiate studies of registry participants, several review processes were required. First, the MASAC review was based on the criteria of scientific merit, study significance, and achievability. Second, review and approval by the principal investigator’s home institutional investigational review board was required. Once such studies were approved, the Data Coordinating Center distributed an invitation to participate and a study description to all eligible registry registrants. The identities of registry members remained unknown to principal investigators unless the prospective study subject contacted the principal investigator expressing willingness to participate.

Data were stored in two databases (INFORMIX; Menlo Park, CA) on a UNIX operating system. To preserve confidentiality, participants’ identifying information was stored in a database separate from the anonymous questionnaire responses. Statistical analyses were performed using computer software (SAS, version 6.12; SAS Institute; Cary, NC).

	Results

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Between May 1997 and June 1999, 7,789 questionnaires were mailed to prospective participants. During this period, 803 completed questionnaires were received by the Data Coordinating Center (response, 10.2%), of which 91 were completed multiple times, leaving 712 unique registrants. The baseline characteristics of these 712 unique participants are presented in Table 1 . Respondents were mostly white, with a mean (± SD) age of 49.8 ± 13.2 years and approximately equal gender distribution (women, 47.7%). Most registrants reported a diagnosis of severe deficiency of ₁-antitrypsin (PI*ZZ phenotype, 70.7%), although 16.4% of participants reported not knowing their phenotype. In the context that most participants were former (73.8%) or current (2.1%) smokers, the majority of respondents (54.2%) reported having emphysema and chronic bronchitis (35%). Because a goal of the first registry questionnaire was to clarify the costs and health-care utilization patterns by individuals with ₁-antitrypsin deficiency, the questionnaire inquired about the number of physician visits over the preceding year, the use of IV augmentation therapy, the receipt of lung volume reduction and/or lung transplantation, and the use of supplemental oxygen (Table 2 ). As shown in Table 2 , the findings indicate a high level of intensity of health-care resource use, with a mean of 7.8 ± 9.4 physician visits over the preceding 12 months. Also, 69.7% of respondents reported ever receiving IV augmentation therapy, and 59.0% reported receiving augmentation therapy currently. As a measure of the severity of lung dysfunction in this relatively young population (mean age, 49.3 years), 35.4% of respondents reported using at least some supplemental oxygen at home.

	Discussion

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As testimony to the success of this registry in promoting participation by large numbers of prospective research subjects, several studies already have been initiated or proposed through the RNR. For example, an ongoing case-control study of occupational risk factors for the development of COPD in ₁-antitrypsin-deficient individuals is being conducted by sampling registry participants with (cases) and without lung dysfunction (controls). In keeping with the confidentiality safeguards of the registry, eligible prospective participants are sent a letter describing the study, a consent form, and the questionnaires and are invited to return the questionnaires to the study investigators. As other examples of studies facilitated by the availability of this registry, applications have been received for an observational study to evaluate psychosocial stressors in ₁-antitrypsin-deficient patients and for a randomized controlled trial of a retinoid in registrants with emphysema. In the context that the registry has been organized only since 1997, the growing number of submitted research applications testifies to the value attached by the scientific community to a registry that allows easy identification of potential research subjects. Furthermore, the fact that > 700 registrants have enrolled in studies from this difficult-to-study population bespeaks the interest by the patient community in facilitating research by direct participation.

While this RNR represents the first instance in which the ₁-antitrypsin-deficient patient community has organized such a research resource, there is precedent for this activity in other diseases. For example, the Cystic Fibrosis Foundation has long maintained a patient registry⁸ and has helped foster centers of clinical excellence in cystic fibrosis care that also have served as investigative sites in multicenter studies. Certainly, many other patient advocacy organizations have previously encouraged research efforts by the more conventional strategy of raising funds for subsequent grant distribution to awardees. The current strategy of enlisting the collaboration of interested clinicians and investigators to work with affected patients to form a research registry advances the mission of the Alpha One Foundation to serve as an active collaborator in research. The successful formation of the registry also affirms that collaboration between the leading patient-advocacy groups, the Alpha One Foundation and the Alpha 1 Association, can rally the support of the patient community for promising studies. Patients obviously support the organizations’ acting as "brokers" on behalf of the patient community with various study sponsors, whether governmental or private.

Recognizing that all registries composed of voluntary subjects may reflect a participation bias, the profile of registrants in the Alpha One Foundation RNR still invites comparison with other cohorts, such as that assembled by the NHLBI Registry for Individuals with Severe Deficiency of ₁-Antitrypsin.^{6 7} In comparing registry findings, distinctions between the current Alpha One Foundation RNR and the NHLBI Registry are noteworthy. Specifically, the purpose of the NHLBI Registry, which began recruitment in 1989 and completed follow-up in 1996, was to characterize the natural history of individuals with severe deficiency of ₁-antitrypsin. Specifically, the rates of decline of lung function and survival were the main outcome measures, for which serial measurements of FEV₁ in all 1,129 participants and careful assessment of all 204 decedents was undertaken. In contrast, the purpose of the Alpha One Foundation RNR, which is a new and separate registry effort, is to characterize the broadest possible population of ₁-antitrypsin-deficient individuals in order to facilitate future studies and to address heretofore unanswered questions (eg, regarding occupational risk factors and the economic burden of having ₁-antitrypsin deficiency). With this background in mind, comparison of the two registry populations shows some similarities and some differences. For example, like the NHLBI Registry, the current cohort is young (mean age Alpha One Foundation RNR, 49.3 years; mean age NHLBI Registry, 46.1 years), mostly white (Alpha One Foundation RNR, 96.2%; NHLBI Registry, 99.2%), of approximately equal gender distribution (Alpha One Foundation RNR, 47.7% women; NHLBI Registry, 45.5% women), and composed mostly of ex-smokers (Alpha One Foundation RNR, 73.3%; NHLBI Registry, 71.6%). Also like the cohort in the NHLBI Registry, most participants reported having emphysema (Alpha One Foundation RNR, 54.2%; NHLBI Registry, 57%), with approximately one third reporting asthma (Alpha One Foundation RNR, 33%; NHLBI Registry, 31%). Indeed, both registries demonstrate the bias of having recruited individuals with more severe disease than the general population of individuals with ₁-antitrypsin deficiency. Specifically, in the NHLBI Registry, 72% of subjects were ascertained because they were symptomatic. In the current registry, the high reported prevalence of emphysema, chronic bronchitis, and asthma (Table 1) bespeaks a similar ascertainment bias.

Unlike the NHLBI Registry group, however, fewer RNR registrants were current smokers (Alpha One Foundation RNR, 7.1%; NHLBI Registry, 8.3%) or reported having liver disease (Alpha One Foundation RNR, 6.4%; NHLBI Registry, 24.7%). Because differences are almost expected in the context of varying strategies for selecting and assembling participants in different cohorts, the common features between different ₁-antitrypsin-deficient cohorts may better reflect universal characteristics of ₁-antitrypsin deficiency. One striking feature of current respondents that reproduces prior experience⁹ is that 16% of respondents in the current registry reported being unaware of their phenotype. This frequency closely resembles the 18.4% prevalence reported in an earlier survey of ₁-antitrypsin-deficient individuals.⁹ Specifically, the results of the earlier 1994 survey of the readership of the Alpha 1 News, the official newsletter of the Alpha 1 Association, suggested that ₁-antitrypsin deficiency was underappreciated by physicians and that affected individuals sometimes demonstrated incomplete knowledge of their own condition.⁹ Notwithstanding the possibility that some affected individuals participated in both the prior survey and the current registry cohort, the persistence of a sizable minority of respondents who report uncertainty about their phenotype suggests that patients’ self-understanding remains incomplete. Because improving self-knowledge about ₁-antitrypsin deficiency is an important aspect of optimizing health behavior, medical therapy, and family well-being, our detection of registry participants who were unaware of their phenotype suggests the need to enhance educational efforts to both the patient and caregiver communities.

In summary, we report the formation and results of a registry of individuals with ₁-antitrypsin deficiency who have identified themselves as willing to be approached for participation in future studies. Already the source of participants in ongoing research, this registry represents the product of collaboration among the patient community, interested scientific advisors, and patient advocacy organizations. Given the significant challenge of conducting research in uncommon illnesses such as ₁-antitrypsin deficiency, we believe the formation of this registry exemplifies an important way in which the patient community can advance its cause of promoting research about pressing, relevant clinical problems.

	Appendix 1

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Medical and Scientific Advisory Committee and Clinical Resource Center Membership in the Alpha One Foundation RNR
MASAC
Mark L. Brantly, MD, Co-Chair, University of Florida College of Medicine, Gainesville, FL; James K. Stoller, MD, FCCP, Co-Chair, Cleveland Clinic Foundation, Cleveland, OH; Alan F. Barker, MD, Oregon Health Sciences University, Portland, OR; Frederick deSerres, PhD, National Institutes of Health, NIEHS, Research Triangle Park, NC; Robert J. Fallat, MD, California Pacific Medical Center, San Francisco, CA; Caroline Riely, MD, University of Tennessee, Memphis, TN; Robert A. Sandhaus, MD, PhD, National Jewish Medical & Research Center, Denver, CO; Gordon L. Snider, MD, Boston Veterans Administration Medical Center, Boston, MA; Charlie Strange, MD, FCCP, Medical University of South Carolina, Charleston, SC; Jeffrey Teckman, MD, Washington University School of Medicine, St. Louis, MO; Gerard M. Turino, MD, Columbia University, College of Physicians & Surgeons, New York, NY; Cathy Valenti, Alpha One Foundation Board of Directors, Meridian, ID; Debbie Waldrop, RN, BSN, CCRC, University of Texas Health Center, Tyler, TX; and John W. Walsh, Alpha One Foundation, Miami, FL.

Bioethics Consultant
Evan DeRenzo, PhD, Center for Ethics/MedStar Health, Rockville, MD.

MASAC Administration
Symma Finn, MA, Alpha One Foundation, Miami, FL.

Prinicipal Investigators at Participating Clinical Resource Centers
Arizona
Richard Helmers, MD, Mayo Clinic, Scottsdale, AZ; and Russell R. Dodge, MD, University of Arizona, Tucson, AZ.

California
Robert J. Fallat, MD, California Pacific Medical Center, San Francisco, CA; Carroll E. Cross, MD, University of California at Davis, Sacramento, CA; Marvin Ament, MD, University of California, Los Angeles Center for Health Sciences, Los Angeles, CA; Donald F. Tierney, MD, University of California, Los Angeles, School of Medicine, Los Angeles, CA; Jack L. Clausen, MD, University of California, San Diego Medical Center, San Diego, CA; and Emmet B. Keeffe, MD, University of Stanford Medical Center, Palo Alto, CA.

Colorado
Robert A. Sandhaus, MD, PhD, National Jewish Medical & Research Center, Denver, CO; and Ronald J. Sokol, MD, The Children’s Hospital, Denver, CO.

Connecticut
Arthur Kotch, MD, Danbury Hospital, Danbury, CT.

Florida
Stephen Grinton, MD, Mayo Clinic Jacksonville, Jacksonville, FL; Mark L. Brantly, MD, University of Florida College of Medicine, Gainesville, FL; and Adam Wanner, MD, University of Miami School of Medicine, Miami, FL.

Indiana
Joseph P. McMahon, MD, Indiana University Medical Center, Indianapolis, IN.

Iowa
Jeff Wilson, MD, University of Iowa, College of Medicine, Iowa City, IA.

Maine
Dermot N. Killian, MD, Mercy Hospital, Portland, ME.

Massachusetts
Steven Weinberger, MD, and Sanjiv Chopra, MD, Beth Israel Hospital; Boston, MA; Frederick Gordon, MD, Lahey Clinic Medical Center, Burlington, MA; and William C. Sheehan, MD, Pulmonary Care, PC, Fall River, MA.

Michigan
Michael S. Eichenhorn, MD, Henry Ford Hospital, Detroit, MI; William F. Bria, MD, University of Michigan Medical Center, Ann Arbor, MI; and K.P. Ravikrishnan, MD, William Beaumont Hospital, Royal Oak, MI.

Minnesota
Michael Krowka, MD, FCCP, Mayo Clinic Rochester, Rochester, MN; Michael K. Porayko, MD, Mayo Clinic Rochester, Rochester, MN; and Marshall Hertz, MD, University of Minnesota Hospital and Clinic, Minneapolis, MN.

Missouri
Jeffrey Teckman, MD, Washington University School of Medicine, St. Louis, MO.

Nebraska
Stephen I. Rennard, MD, FCCP, University of Nebraska Medical Center, Omaha, NE.

New York
Henry C. Bodenheimer, Jr., MD, Mount Sinai Medical Center, New York, NY; Frederick J. Suchy, MD, Mount Sinai School of Medicine, New York, NY; Edward Eden, MD, St. Lukes/Roosevelt Hospital Center, New York, NY; and Richard W. Hyde, MD, University of Rochester Medical Center, Rochester, NY.

North Carolina
James F. Donohue, MD, FCCP, University of North Carolina, Chapel Hill, NC.

Ohio
William F. Balistreri, MD, Children’s Hospital Medical Center, Cincinnati, OH; James K. Stoller, MD, FCCP, and Zobair Younossi, MD, Cleveland Clinic Foundation, Cleveland, OH; Kevin D. Mullen, MD, MetroHealth Medical Center, Cleveland, OH; and Mark D. Wewers, MD, Ohio State University, Columbus, OH.

Oregon
Alan F. Barker, MD, Oregon Health Sciences University, Portland, OR.

South Carolina
Charlie Strange, MD, FCCP, and Marc Judson, MD, FCCP, Medical University of South Carolina, Charleston, SC.

Tennessee
Norman T. Soskel, MD, Memphis Tennessee Clinical Center, Memphis, TN; and Caroline Riely, MD, University of Tennessee, Memphis, TN.

Texas
W. John Ryan, MD, Dallas Pulmonary Associates, Dallas, TX; and James M. Stocks, MD, University of Texas Health Center, Tyler, TX.

Utah
Edward J. Campbell, MD, and Richard E. Kanner, MD, University of Utah Health Sciences Center, Salt Lake City, UT.

Washington
Robert E. Sandblom, MD, Eastside Specialty Center, Redmond, WA.

Affiliated Research Centers
Christine Cannon, RN, PhD, University of Delaware, Newark, DE, and William F. Brechue, PhD, Indiana University, Bloomington, IN.

	Footnotes

 
Abbreviations: MASAC = Medical and Scientific Advisory Committee; NHLBI = National Heart, Lung, and Blood Institute; RNR = Research Network Registry

{altfoot}*From the Department of Pulmonary Medicine (Dr. Stoller), Division of Medicine, Section of Respiratory Therapy, The Cleveland Clinic Foundation, Cleveland, OH; Division of Pulmonary Medicine (Dr. Brantly), University of Florida, College of Medicine, Gainesville, FL; Department of Epidemiology and Public Health (Dr. Fleming), University of Miami, School of Medicine, Miami, FL; Biostatistics Program (Dr. Bean), Children’s Hospital Medical Center, Cincinnati, OH; and the Alpha One Foundation (Mr. Walsh), Miami, FL.

This research was funded by the Alpha One Foundation.

Received for publication October 11, 1999. Accepted for publication March 22, 2000.

	References

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