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Asthma outcomes workshop: Overview

      Background

      Asthma clinical research will highly benefit from standardization of major outcomes in terms of definition and assessment methodology. This will permit useful comparisons across interventional or observational studies and will allow more effective data sharing.

      Objective

      National Institutes of Health (NIH) institutes and the Agency for Healthcare Research and Quality convened a workshop involving 7 expert subcommittees to propose which asthma outcomes should be assessed with standardized methodology in future asthma clinical research studies.

      Methods

      Each subcommittee utilized comprehensive literature reviews and expert opinion to compile a list of asthma outcomes and classified them as either core (required in future studies), supplemental (to be used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.

      Results

      Outcomes for study participant characterization, as well as for prospective clinical trial intervention and observational studies, were proposed for adults and children, and methodologies for outcome collection and reporting were determined. Furthermore, the workshop identified areas in which new outcomes or instruments for their measurement need to be developed and validated.

      Conclusions

      Standardized outcomes for clinical research in asthma have been proposed. Participating NIH institutes and other federal agencies will consider these recommendations in future clinical research initiatives in asthma.

      Key words

      Abbreviations used:

      ATS (American Thoracic Society), EC (Executive Committee), ERS (European Respiratory Society), Feno (Fractional exhaled nitric oxide), NIH (National Institutes of Health), PROMIS (Patient Report Outcomes Measurement System)
      Asthma is a major public health problem that affects almost 25 million Americans.
      • Akinbami L.J.
      • Moorman J.E.
      • Liu X.
      Asthma prevalence, health care use, and mortality: United States, 2005-2009.
      Clinical research, including clinical trials,
      NIH definition of clinical research: Patient-oriented research, including epidemiologic and behavioral studies, outcomes research, and health services research. Patient-oriented research is research conducted with human subjects (or on material of human origin, such as tissues, specimens, and cognitive phenomena) in which a researcher directly interacts with human subjects. It includes research on mechanisms of human disease, therapeutic interventions, clinical trials, and development of new technologies but does not include in vitro studies using human tissues not linked to a living individual. Studies falling under 45 CFR 46.101(b) (4) are not considered clinical research for purposes of this definition. NIH definition of clinical trial: A biomedical or behavioral research study of human subjects designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. (http://grants.nih.gov/grants/glossary.htm)
      NIH definition of clinical research: Patient-oriented research, including epidemiologic and behavioral studies, outcomes research, and health services research. Patient-oriented research is research conducted with human subjects (or on material of human origin, such as tissues, specimens, and cognitive phenomena) in which a researcher directly interacts with human subjects. It includes research on mechanisms of human disease, therapeutic interventions, clinical trials, and development of new technologies but does not include in vitro studies using human tissues not linked to a living individual. Studies falling under 45 CFR 46.101(b) (4) are not considered clinical research for purposes of this definition. NIH definition of clinical trial: A biomedical or behavioral research study of human subjects designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. (http://grants.nih.gov/grants/glossary.htm)
      in asthma is supported by various governmental and nongovernmental organizations, as well as the pharmaceutical industry. It is well recognized that clinical research in asthma will highly benefit from standardization of the major clinical outcomes in terms of definition and assessment methodology. Such standardization will permit useful comparisons across interventional or observational clinical studies, genome-wide association studies, and data sharing.

      Objectives

      An Asthma Outcomes workshop was convened in Bethesda, Md, on March 15 and 16, 2010, by a consortium of several National Institutes of Health (NIH) institutes and the Agency for Healthcare Research and Quality. The 2 key objectives of the workshop were (1) to establish standard definitions and data collection methodologies for validated outcome measures in asthma clinical research with the goal of enabling comparisons across asthma research studies and clinical trials and (2) to identify promising outcome measures for asthma clinical research and comment on their status and further validation needs.
      The participating federal agencies will consider the recommendations of the workshop report to identify a selective set of outcomes that will be required outcome measures in agency-initiated asthma clinical research programs, including clinical trials, observational/cross-sectional studies, and genetic studies. This will accelerate the widespread use of the data produced by asthma clinical research by permitting meaningful comparative analyses and enhancing the level of confidence in the research findings. It also will help promote the translation of research into clinical practice and health policy.
      This Asthma Outcomes workshop report, which consists of 7 individual articles, represents the recommendations of the workshop participants for core, supplemental, and emerging outcomes, as defined below, for 7 domains of asthma clinical research outcome measures: biomarkers, composite scores of asthma control, exacerbations, healthcare utilization and costs, pulmonary physiology, quality of life, and symptoms.
      • 1.
        Core asthma outcome measures: a selective set of asthma outcomes to be considered as requirements in the funding of NIH-initiated asthma clinical trials and large observational studies. The criteria for identifying these outcomes were (1) inclusion of the most important clinical aspects of asthma, (2) evidence of the outcome’s validity, and (3) potential for the standardization of the outcome to enable homogeneous meta-analyses across studies and promote translation of research into clinical practice and health policy. In addition, core outcomes need to be safely and easily obtained and affordable for clinical studies involving large numbers of participants. Core outcomes are not to be confused with the primary outcomes of a clinical study. Depending on study design, a core outcome also may play a primary outcome role; however, the purpose of core outcomes is to allow for cross-study harmonization, as described above, whether the outcomes of interest are related to primary or secondary research aims.
      • 2.
        Supplemental asthma outcome measures: asthma outcomes for which standard definitions can or have been developed, methods for measurement can be specified, and validity has been proved but whose inclusion in funded clinical asthma research will be optional. Such outcomes may only apply to some forms of clinical research or may be too cumbersome or expensive for inclusion in all studies.
      • 3.
        Emerging asthma outcome measures: asthma outcomes that have the potential (1) to expand and/or improve current aspects of disease monitoring and (2) to improve translation of basic and animal model-based asthma research into clinical research. Emerging asthma outcomes may be new or may have been previously used in asthma clinical research but are not yet standardized and require further development and validation.
      The responsibility for the workshop report and recommendations is solely that of the Planning Committee and subcommittee members. The workshop report is not an official document of any government agency.

      Members of the workshop

      The Asthma Outcomes workshop was organized by a consortium of governmental and nongovernmental organizations, including the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network. Representatives of the above organizations formed a Planning Committee that had the overall responsibility for the workshop.
      The Planning Committee selected the workshop cochairs and invited 79 asthma researchers to serve on subcommittees reflecting 7 domains of asthma outcomes, as described above. The Planning Committee also selected 2 cochairs for each subcommittee. Recognizing the various perspectives that might influence the selection of outcome measures, the Planning Committee ensured that each subcommittee had representatives from the specialties of adult asthma, pediatric asthma, pulmonology, and allergy/immunology. Furthermore, representatives from the fields of pharmacology, biostatistics, primary care, and behavioral/social science were included in the subcommittee membership.
      The cochairs of each subcommittee and the Planning Committee members served as the Executive Committee (EC) to organize development of the workshop report and meeting discussions and review and approve the final workshop report. To contribute to the evaluation of the subcommittees’ draft reports during the March 2010 workshop discussions, the EC invited 2 additional groups: (1) discussants to present critiques of the subcommittee reports at the workshop from either the perspective of an asthma clinical researcher or an end user of research findings, such as groups involved in quality improvement, guidelines development, or health policy, and (2) representatives from other federal agencies with asthma programs, the pharmaceutical industry, healthcare policy groups, and lay voluntary organizations. A list of workshop participants, denoting cochairs, Planning Committee members, subcommittee members, discussants, and participant observers is presented in Table I. All comments by nonsubcommittee participants at the workshop were considered, but the responsibility for the workshop report and recommendations is solely that of the Planning Committee and subcommittee members.
      Table IAsthma outcomes workshop participants
      Co-Chairs
      William Busse, MD

      University of Wisconsin, Madison

      Wayne Morgan, MD

      University of Arizona, Tucson
      Virginia Taggart, MPH

      National Heart, Lung, and Blood Institute

      Alkis Togias, MD

      National Institute of Allergy and Infectious Diseases
      Planning Committee Members
      Julie Bamdad, MSE

      National Heart, Lung, and Blood Institute

      Carol Blaisdell, MD, MEd

      National Heart, Lung, and Blood Institute

      Denise Dougherty, PhD

      Agency for Healthcare Research and Quality

      T. J. Dunlap

      Merck Childhood Asthma Network, Inc

      Peter Gergen, MD, MPH

      National Institute of Allergy and Infectious Diseases

      Floyd Malveaux, MD, PhD

      Merck Childhood Asthma Network, Inc

      J. Patrick Mastin, PhD

      National Institute of Environmental Health Sciences
      Michael Minnicozzi, PhD

      National Institute of Allergy and Infectious Diseases

      Julie Schwaninger, MS

      National Institute of Allergy and Infectious Diseases

      Robert A. Smith, PhD

      National Heart, Lung, and Blood Institute

      Perdita Taylor-Zapata, MD

      Eunice Kennedy Shriver National Institute of Child Health and Human Development

      P. Jonathan White, MD

      Agency for Healthcare Research and Quality

      Anne Zajicek, MD, PharmD

      Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Workshop Subcommittee Members
      Lara J. Akinbami, MD

      Centers for Disease Control and Prevention

      Andrea J. Apter, MSc, MA, MD

      University of Pennsylvania

      Homer A. Boushey, MD

      University of California, San Francisco

      Robert Brown, MD, MPH

      Johns Hopkins University

      Michael D. Cabana, MD, MPH

      University of California, San Francisco

      Carlos A. Camargo, Jr, MD, DrPH

      Massachusetts General Hospital

      Jonathan D. Campbell, PhD, MS

      University of Colorado

      Glorisa J. Canino, MD, PhD

      University of Puerto Rico

      Mario Castro, MD, MPH

      Washington University in St Louis

      Noreen Clark, PhD

      University of Michigan

      Michelle M. Cloutier, MD

      University of Connecticut

      Ronina Covar, MD

      National Jewish Health

      Kurtis S. Elward, MD, MPH

      Family Medicine of Albermarle

      Serpil C. Erzurum, MD

      Cleveland Clinic Foundation

      John V. Fahy, MD, MSc

      University of California, San Francisco

      Michael B. Foggs, MD

      Advocate Medical Group of Advocate Health Care

      Anne Fuhlbrigge, MD, MS

      Brigham and Women’s Hospital

      James Gern, MD

      University of Wisconsin

      Robert W. Grundmeier, MD

      Children’s Hospital of Philadelphia

      Jill S. Halterman, MD, MPH

      University of Rochester

      Robert G. Hamilton, PhD

      Johns Hopkins University

      Tina V. Hartert, MD, MPH

      Vanderbilt University

      Peter W. Heymann, MD

      University of Virginia

      John F. Hunt, MD

      University of Virginia

      Charles G. Irvin, PhD

      University of Vermont

      Meyer Kattan, MD

      Columbia University

      H. William Kelly, PharmD

      University of New Mexico

      Carolyn M. Kercsmar, MD, MS

      Cincinnati Children’s Hospital

      Hirohito Kita, MD

      Mayo Clinic Rochester

      Monica Kraft, MD

      Duke University

      Jerry A. Krishnan, MD, PhD

      University of Illinois at Chicago

      Todd A. Lee, PharmD, PhD

      University of Illinois at Chicago
      Robert F. Lemanske, Jr, MD

      University of Wisconsin

      Andrew H. Liu, MD

      National Jewish Health

      Mark C. Liu, MD

      Johns Hopkins University

      Rita Mangione-Smith, MD, MPH

      University of Washington

      Fernando D. Martinez, MD

      University of Arizona, Tucson

      Elizabeth C. Matsui, MD, MHS

      Johns Hopkins University

      David Mauger, PhD

      Penn State University College of Medicine

      Herman Mitchell, PhD

      Rho Federal Systems Division, Inc

      George T. O’Connor, MD, MS

      Boston University

      Lynn Olson, PhD

      American Academy of Pediatrics

      Reynold A. Panettieri, Jr, MD

      University of Pennsylvania Medical Center

      David Peden, MD, MS

      University of North Carolina at Chapel Hill

      Stephen P. Peters, MD, PhD

      Wake Forest University

      Cynthia S. Rand, PhD

      Johns Hopkins University

      Michael Schatz, MD, MS

      Kaiser Permanente

      Robert P. Schleimer, PhD

      Northwestern University

      James R. Sheller, MD

      Vanderbilt University

      Christine Sorkness, PharmD

      University of Wisconsin

      Ronald Sorkness, MS, PhD, RPh

      University of Wisconsin

      Stuart Stoloff, MD

      Independent Family Practice

      Carson City, Nevada

      Sean D. Sullivan, PhD, MSc

      University of Washington

      E. Rand Sutherland, MD, MPH

      National Jewish Health

      Stanley J. Szefler, MD

      National Jewish Health

      William G. Teague, MD

      University of Virginia

      Robert S. Tepper, MD, PhD

      Indiana University

      James Tonascia, PhD

      Johns Hopkins Center for Clinical Trials

      William M. Vollmer, PhD

      Kaiser Permanente

      Sally Wenzel, MD

      University of Pittsburgh

      Sandra R. Wilson, PhD

      Palo Alto Medical Foundation Research Institute

      Robert S. Wise, MD

      Johns Hopkins University

      Rosalind J. Wright, MD, MPH

      Harvard Medical School
      Workshop Discussants
      Bruce Bender, PhD

      National Jewish Health

      Thomas Casale, MD

      Creighton University

      Rosanna Coffey, PhD

      Thomson Reuters (Healthcare), Inc

      Gregory Diette, MD, MHS

      Johns Hopkins University

      Theresa Guilbert, MD

      University of Wisconsin

      Elliot Israel, MD

      Harvard Medical School

      Tracy Lieu, MD, MPH

      Harvard Medical School

      Carole Ober, PhD

      University of Chicago
      Paul O’Byrne, MB, FRCP(C)

      McMaster University

      Cecilia Patino, MD

      University of Southern California

      Thomas A. E. Platts-Mills, MD, PhD

      University of Virginia

      Helen Reddel, MB, BS, PhD

      Woolcock Institute of Medical Research

      Richard Shiffman, MD, MCIS

      Yale University

      James Stout, MD, MPH

      University of Washington

      Kelan Tantisira, MD, MPH

      Harvard Medical School

      Stephen Teach, MD, MPH

      Children’s National Medical Center

      Edward Zoratti, MD

      Henry Ford Health System
      Workshop Participant Observers
      M. Beth Benedict, DrPH, JD, RN

      Centers for Medicare & Medicaid Services

      Frederick Bode, MD

      Sepracor, Inc

      Mary Brasler, EdD, MSN

      Asthma and Allergy Foundation of America

      Debera Brown

      Asthmatx, Inc

      Rebekah Buckley, MPH, CRT

      Centers for Disease Control and Prevention

      Franklin Cerasoli, PhD

      Pfizer, Inc

      Badrul A. Chowdhury, MD, PhD

      Food and Drug Administration

      Thomas Croxton, PhD, MD

      National Heart, Lung, and Blood Institute

      Irene Dankwa-Mullan, MD, MPH

      National Center on Minority Health and Health Disparities

      Yamo Deniz, MD

      Hoffmann-La Roche, Inc

      David Diaz-Sanchez

      US Environmental Protection Agency

      Norman Edelman, MD

      American Lung Association

      Basil Eldadah, MD, PhD

      National Institute on Aging

      Matthew Fenton, PhD

      National Institute of Allergy and Infectious Diseases

      Robinson Fulwood, PhD, MSPH

      National Heart, Lung, and Blood Institute

      Paul Garbe, DVM, MPH

      National Center for Environmental Health

      Centers for Disease Control and Prevention

      Margarita Gomez, MD

      National Institute of Allergy and Infectious Diseases

      Karen Huss, PhD, MSN, RN

      National Institute of Nursing Research

      James Kiley, PhD

      National Heart, Lung, and Blood Institute
      Deborah Kilstein, BSN, MBA, JD

      Association for Community Affiliated Plans

      Monroe King, DO

      National Institute on Aging

      Kathy L. Lampl, MD

      AstraZeneca Pharmaceuticals

      Shao-Lee Lin, MD, PhD

      Amgen, Inc

      Soeren Mattke, MD, DSc

      RAND Corporation

      Patricia Noel, PhD

      National Heart, Lung, and Blood Institute

      Steve Pascoe, PhD

      Novartis Pharma AG

      Marshall Plaut, MD

      National Institute of Allergy and Infectious Diseases

      Zhaoxia Ren, MD, PhD

      Eunice Kennedy Shriver National Institute of Child Health and Human Development

      Daniel Rotrosen, MD

      National Institute of Allergy and Infectious Diseases

      Nancy Santanello, MD, MS

      Merck Research Laboratories

      Diana Schmidt, BS, MPH

      National Heart, Lung, and Blood Institute

      Philip Silkoff, MD, MBBS, MRCP

      Centocor R&D, Inc

      Liz Sloss, PhD

      RAND Health

      Alisa Smith, PhD

      US Environmental Protection Agency

      David Stempel, MD

      GlaxoSmithKline

      Eileen Storey, MD, MPH

      National Institute for Occupational Safety and Health

      Gail Weinmann, MD

      National Heart, Lung, and Blood Institute

      Carol Wilhoit, MD, MS

      Blue Cross Blue Shield of Illinois

      Development of the workshop report

      The workshop report is comprised of 7 individual articles, 1 from each subcommittee. Each subcommittee met through frequent telephone conference calls and e-mail exchanges over the course of 9 months to prepare a draft report on its respective topic. The subcommittees were responsible for defining the scope of their topic, conducting appropriate literature reviews, drafting their report and recommendations for discussion by all workshop participants, and revising their report following the workshop. Through a contract funded by contributions of the Planning Committee participant organizations, RAND Health of the RAND Corporation conducted 1 systematic review of the literature for each subcommittee, according to the respective subcommittee’s request. The literature was from peer-reviewed scientific publications in the English language published through March 2010.
      Each subcommittee also discussed the relevant section of the American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Asthma Control and Exacerbations—Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice
      • Reddel H.K.
      • Taylor D.R.
      • Bateman E.D.
      • Boulet L.P.
      • Boushey H.A.
      • Busse W.W.
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
      (hereafter referred to as the ATS/ERS Statement) at the beginning of its work. Subcommittees built on the ATS/ERS statement as much as possible to develop their recommendations as to core, supplemental, and emerging asthma outcomes for future NIH research.
      The EC met through monthly telephone conference calls to provide overall direction and coordination to the subcommittees, provide general templates for the preparation of each subcommittee’s report, help ensure consistency, and organize the workshop meeting. At the workshop, each subcommittee’s draft report was discussed at length by all workshop participants. After the workshop, the subcommittees revised their reports and produced the articles of this journal supplement. The EC met by telephone conference call to review and approve each subcommittee’s final recommendations.

      Support

      Contributions from the organizations represented on the Planning Committee and a grant from the Robert Wood Johnson Foundation provided all funds for the literature searches, travel, lodging, and conference logistics for workshop cochairs Drs Busse and Morgan, subcommittee members, and discussants. All other meeting participants travelled at their own expense. Contributions from National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Environmental Health Sciences; and US Environmental Protection Agency provided support for publication of the workshop report.

      Key recommendations

      • A summary of the key workshop proposals for core and supplemental measures are presented in Table II, Table III, Table IV, Table V. Each subcommittee’s individual article provides discussion and references to the scientific literature that support these recommendations.
        Table IIRecommendations for core asthma outcomes for NIH-initiated clinical research for adults and adolescents (≥12 years of age)
        Characterization of study population for prospective clinical trials (ie, baseline information)Prospective clinical trial efficacy/effectiveness outcomesObservational study outcomes
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        BiomarkersSerologic multiallergen screen (IgE) to define atopic status (also for observational studies)NoneNone
        Composite scoresEither ACQ or ACTEither ACQ or ACTEither ACQ or ACT
        ExacerbationsEvents in the 12 months prior to study entry:
        • 1.
          Systemic corticosteroids for asthma
        • 2.
          Asthma-specific hospital admissions
        • 3.
          Asthma-specific ED visits (separate UC visits when these can be differentiated)
        • 1.
          Systemic corticosteroids for asthma for at least 3 days
        • 2.
          Asthma-specific hospital admissions
        • 3.
          Asthma-specific ED visits (separate UC visits when these can be differentiated)
        • 4.
          Asthma-specific ICU admissions/intubations
        • 5.
          Death (all cause and asthma related)
        • 1.
          Systemic corticosteroids for asthma
        • 2.
          Asthma-specific hospital admissions
        • 3.
          Asthma-specific ED visits (separate UC visits when these can be differentiated)
        Healthcare utilization and costsHistory of:
        • 1.
          Asthma-specific hospital admissions
        • 2.
          Asthma-specific ED visits
        • 3.
          Asthma-specific outpatient visits
        • 4.
          Asthma-specific medication use
        • 1.
          Asthma-specific hospital admissions
        • 2.
          Asthma-specific ED visits
        • 3.
          Asthma-specific outpatient visits
        • 4.
          Asthma-specific detailed medication use (name, dose, and duration)
        • 5.
          Resource use related to the intervention (eg, personnel time, mite eradication, and equipment)
        • 1.
          Asthma-specific hospital admissions
        • 2.
          Asthma-specific ED visits
        • 3.
          Asthma-specific outpatient visits
        • 4.
          Asthma-specific detailed medication use (name, dose, and duration)
        • 5.
          Resource use related to the intervention (eg, personnel time, mite eradication, and equipment)
        Pulmonary physiologySpirometry (prebronchodilator and postbronchodilator)Spirometry (without bronchodilator)Spirometry (prebronchodilator and postbronchodilator)
        Quality of lifeNoneNoneNone
        SymptomsNoneNoneNone
        Note: For a detailed presentation and discussion of each of these outcomes, the methodology for measurement, and supporting bibliographic references, see the respective article in this supplement.
        ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; ED, emergency department; ICU, intensive care unit; UC, urgent care.
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        Table IIIRecommendations for core asthma outcomes for NIH-initiated clinical research for children (5-11 years of age)
        Only some of these outcomes are suitable for children 0 to 4 years of age.
        Characterization of study population for prospective clinical trials (ie, baseline information)Prospective clinical trial efficacy/effectiveness outcomesObservational study outcomes
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        BiomarkersSerologic multiallergen screen (IgE) to define atopic status (also for observational studies)NoneNone
        Composite scorescACTNonecACT
        ExacerbationsEvents in the 12 months prior to study entry:
        • 1.
          Systemic corticosteroids for asthma
        • 2.
          Asthma-specific hospital admissions
        • 3.
          Asthma-specific ED visits (separate UC visits where these can be differentiated)
        • 1.
          Systemic corticosteroids for asthma
        • 2.
          Asthma-specific hospital admissions
        • 3.
          Asthma-specific ED visits (separate UC visits when these can be differentiated)
        • 4.
          Asthma-specific ICU admissions/intubations
        • 5.
          Death (all cause and asthma related)
        • 1.
          Systemic corticosteroids for asthma
        • 2.
          Asthma-specific hospital admissions
        • 3.
          Asthma-specific ED visits (separate UC visits when these can be differentiated)
        Healthcare utilization and costsHistory of:
        • 1.
          Asthma-specific hospital admissions
        • 2.
          Asthma-specific ED visits
        • 3.
          Asthma-specific outpatient visits
        • 4.
          Asthma-specific medication use
        • 1.
          Asthma-specific hospital admissions
        • 2.
          Asthma-specific ED visits
        • 3.
          Asthma-specific outpatient visits
        • 4.
          Asthma-specific detailed medication use (name, dose, and duration)
        • 5.
          Resource use related to the intervention (eg, personnel time, mite eradication, and equipment)
        • 1.
          Asthma-specific hospital admissions
        • 2.
          Asthma-specific ED visits
        • 3.
          Asthma-specific outpatient visits
        • 4.
          Asthma-specific detailed medication use (name, dose, and duration)
        • 5.
          Resource use related to the intervention (eg, personnel time, mite eradication, and equipment)
        Pulmonary physiologySpirometry (prebronchodilator and postbronchodilator)Spirometry (without bronchodilator)Spirometry (prebronchodilator and postbronchodilator)
        Quality of lifeNoneNoneNone
        SymptomsNoneNoneNone
        Note: For a detailed presentation and discussion of each of these outcomes, the methodology for measurement, and supporting bibliographic references, see the respective article in this supplement.
        cACT, Childhood Asthma Control Test; ED, emergency department; ICU, intensive care unit; UC, urgent care.
        Only some of these outcomes are suitable for children 0 to 4 years of age.
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        Table IVRecommendations for supplemental asthma outcomes for NIH-initiated clinical research for adults
        Only some of these outcomes are also suitable for adolescents.
        Characterization of study population for prospective clinical trials (ie, baseline information)Prospective clinical trial efficacy/effectiveness outcomesObservational study outcomes
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        Biomarkers
        • 1.
          Feno
        • 2.
          Sputum eosinophils
        • 3.
          CBC (total eosinophils)
        • 4.
          Total IgE
        • 5.
          Allergen-specific IgE
        • 6.
          Urinary LTE4
        • 1.
          Feno
        • 2.
          Sputum eosinophils
        • 3.
          CBC (total eosinophils)
        • 4.
          Total IgE
        • 5.
          Allergen-specific IgE
        • 6.
          Urinary LTE4
        • 1.
          Feno
        • 2.
          Sputum eosinophils
        • 3.
          CBC (total eosinophils)
        • 4.
          Total IgE
        • 5.
          Allergen-specific IgE
        • 6.
          Urinary LTE4
        Composite scoresATAQ in studies of healthcare utilizationNoneATAQ in studies of healthcare utilization
        Exacerbations
        • 1.
          For trials in the acute management of exacerbations (ED setting): FEV1
        • 2.
          Any prior exacerbation
        • 3.
          Any prior ICU admission/intubation
        • 4.
          SES of the study population
        • 1.
          For trials of acute management of exacerbations (ED setting): FEV1
        None
        Healthcare utilization and costs
        • 1.
          Categorization of asthma-specific outpatient visits:
          • A.
            Primary care
            • I.
              Scheduled
            • II.
              Unscheduled
          • B.
            Specialty care
            • I.
              Scheduled
            • II.
              Unscheduled
        • 2.
          Respiratory healthcare use (eg, pneumonia and bronchitis)
        • 3.
          Asthma school absences
        • 4.
          Asthma work absences
        • 1.
          Categorization of asthma-specific outpatient visits:
          • A.
            Primary care
            • I.
              Scheduled
            • II.
              Unscheduled
          • B.
            Specialty care
            • I.
              Scheduled
            • II.
              Unscheduled
        • 2.
          Respiratory healthcare use
        • 3.
          Asthma school absences
        • 4.
          Asthma work presenteeism and absenteeism (WPAI instrument)
        • 5.
          Cost analysis and cost-effectiveness analysis
        • 1.
          Categorization of asthma-specific outpatient visits:
          • A.
            Primary care
            • I.
              Scheduled
            • II.
              Unscheduled
          • B.
            Specialty care
            • I.
              Scheduled
            • II.
              Unscheduled
        • 2.
          Respiratory healthcare use
        • 3.
          Asthma school absences
        • 4.
          Asthma work presenteeism and absenteeism (WPAI instrument)
        • 5.
          Cost analysis and cost-effectiveness analysis
        Pulmonary physiology
        • 1.
          PEF monitoring
        • 2.
          Airway responsiveness
          Methacholine inhalation and exercise challenge.
        • 3.
          Lung volumes
        • 4.
          Gas exchange
          Pulmonary diffusing capacity; arterial blood gases and pulse oximetry.
        • 1.
          PEF monitoring
        • 2.
          Airway responsiveness
          Methacholine inhalation and exercise challenge.
        • 3.
          Lung volumes
        • 4.
          Spirometry (prebronchodilator and postbronchodilator)
        • 5.
          Gas exchange
          Pulmonary diffusing capacity; arterial blood gases and pulse oximetry.
        • 1.
          PEF monitoring
        • 2.
          Airway responsiveness
          Methacholine inhalation and exercise challenge.
        • 3.
          Lung volumes
        • 4.
          Gas exchange§
        Quality of lifeABP

        AIS-6

        AQLQ-S

        Mini-AQLQ

        LWAQ

        Modified AQLQ-Marks

        SGRQ

        AQ-20
        ABP

        AIS-6

        AQLQ-S

        Mini-AQLQ

        LWAQ

        Modified AQLQ-Marks

        SGRQ

        AQ-20
        ABP

        AIS-6

        AQLQ-S

        Mini-AQLQ

        LWAQ

        Modified AQLQ-Marks

        SGRQ

        AQ-20
        Symptoms
        • 1.
          ASUI (retrospective questionnaire)
        • 2.
          Daytime Symptom Diary Scale and Nocturnal Diary Scale (daily diary)
        • 1.
          ASUI (retrospective questionnaire)
        • 2.
          Daytime Symptom Diary Scale and Nocturnal Diary Scale (daily diary)
        • 1.
          ASUI (retrospective questionnaire)
        • 2.
          Daytime Symptom Diary Scale and Nocturnal Diary Scale (daily diary)
        Note: For a detailed presentation and discussion of each of these outcomes, the methodology for measurement, and supporting bibliographic references, see the respective article in this supplement.
        ABP, Asthma Bother Profile; AIS-6, Asthma Index Survey; AQ-20, Airways Questionnaire-20; AQLQ-S, Asthma Quality of Life Questionnaire-Standardized; ASUI, Asthma Symptom Utility Index; ATAQ, Asthma Therapy Assessment Questionnaire; CBC, complete blood count; ED, emergency department; Feno, fractional exhaled nitric oxide; ICU, intensive care unit; LTE4, leukotriene E4; LWAQ, Living With Asthma Questionnaire; Mini-AQLQ, Mini Asthma Quality of Life Questionnaire; Modified AQLQ-Marks, Modified Asthma Quality of Life Questionnaire-Marks; PEF, peak expiratory flow; SES, socioeconomic status; SGRQ, St George’s Respiratory Questionnaire; WPAI, Work Productivity and Activity Impairment Questionnaire.
        Only some of these outcomes are also suitable for adolescents.
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        Methacholine inhalation and exercise challenge.
        § Pulmonary diffusing capacity; arterial blood gases and pulse oximetry.
        Table VRecommendations for supplemental asthma outcomes for NIH-initiated clinical research for children
        Only some of these outcomes are also suitable for children 0 to 4 years of age.
        Characterization of study population for prospective clinical trials (ie, baseline information)Prospective clinical trial efficacy/effectiveness outcomesObservational study outcomes
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        Biomarkers
        • 1.
          Feno
        • 2.
          Sputum eosinophils
        • 3.
          CBC (total eosinophils)
        • 4.
          Total IgE
        • 5.
          Allergen-specific IgE
        • 6.
          Urinary LTE4
        • 1.
          Feno
        • 2.
          Sputum eosinophils
        • 3.
          CBC (total eosinophils)
        • 4.
          Total IgE
        • 5.
          Allergen-specific IgE
        • 6.
          Urinary LTE4
        • 1.
          Feno
        • 2.
          Sputum eosinophils
        • 3.
          CBC (total eosinophils)
        • 4.
          Total IgE
        • 5.
          Allergen-specific IgE
        • 6.
          Urinary LTE4
        Composite scoresNonecACTNone
        Exacerbations
        • 1.
          For trials in the acute management of exacerbations (ED setting):
          • A.
            Validated assessment tools, such as PASS, PS, PRAM, CAS, PI, ASS
          • B.
            FEV1 (ages 5-11 years, as feasible)
        • 2.
          Any prior exacerbation
        • 3.
          Any prior ICU admission/intubation
        • 4.
          SES of the study population
        • For trials in the acute management of exacerbations (ED setting):
          • A.
            Validated assessment tools such as PASS, PS, PRAM, CAS, PI, ASS
          • B.
            FEV1 (ages 5-11 years, as feasible)
        None
        Healthcare utilization and costs
        • 1.
          Categorization of asthma-specific outpatient visits:
          • A.
            Primary care
            • I.
              Scheduled
            • II.
              Unscheduled
          • B.
            Specialty care
            • I.
              Scheduled
            • II.
              Unscheduled
        • 2.
          Respiratory healthcare use (eg, pneumonia and bronchitis)
        • 3.
          Asthma school absences
        • 4.
          Asthma work absences
        • 1.
          Categorization of asthma-specific outpatient visits:
          • A.
            Primary care
            • I.
              Scheduled
            • II.
              Unscheduled
          • B.
            Specialty care
            • I.
              Scheduled
            • II.
              Unscheduled
        • 2.
          Respiratory healthcare use
        • 3.
          Asthma school absences
        • 4.
          Asthma work presenteeism and absenteeism (WPAI instrument)
        • 5.
          Cost analysis and cost-effectiveness analysis
        • 1.
          Categorization of asthma-specific outpatient visits:
          • A.
            Primary care
            • I.
              Scheduled
            • II.
              Unscheduled
          • B.
            Specialty care
            • I.
              Scheduled
            • II.
              Unscheduled
        • 2.
          Respiratory healthcare use
        • 3.
          Asthma school absences
        • 4.
          Asthma work presenteeism and absenteeism (WPAI instrument)
        • 5.
          Cost analysis and cost-effectiveness analysis
        Pulmonary physiology
        • 1.
          PEF monitoring
        • 2.
          Airway responsiveness
          Methacholine inhalation and exercise challenge (children aged 5 to 7 years are less likely to perform well on these tests).
        • 3.
          Lung volumes
        • 4.
          Gas exchange
          Pulmonary diffusing capacity (breath holding is difficult in children aged 5-7 years); arterial blood gases and pulse oximetry.
        • 1.
          PEF monitoring
        • 2.
          Airway responsiveness
          Methacholine inhalation and exercise challenge (children aged 5 to 7 years are less likely to perform well on these tests).
        • 3.
          Lung volumes
        • 4.
          Spirometry (prebronchodilator and postbronchodilator)
        • 5.
          Gas exchange
          Pulmonary diffusing capacity (breath holding is difficult in children aged 5-7 years); arterial blood gases and pulse oximetry.
        • 1.
          PEF monitoring
        • 2.
          Airway responsiveness
          Methacholine inhalation and exercise challenge (children aged 5 to 7 years are less likely to perform well on these tests).
        • 3.
          Lung volumes
        • 4.
          Gas exchange
          Pulmonary diffusing capacity (breath holding is difficult in children aged 5-7 years); arterial blood gases and pulse oximetry.
        Quality of life
        • 1.
          CHSA
        • 2.
          PAQLQ
        • 3.
          Pediatric Caregiver AQLQ
        • 4.
          PedsQL 3.0, Asthma Module
        • 1.
          CHSA
        • 2.
          PAQLQ
        • 3.
          Pediatric Caregiver AQLQ
        • 4.
          PedsQL 3.0, Asthma Module
        • 1.
          CHSA
        • 2.
          PAQLQ
        • 3.
          Pediatric Caregiver AQLQ
        • 4.
          PedsQL 3.0, Asthma Module
        SymptomsPACD (daily diary)PACD (daily diary)PACD (daily diary)
        Note: For a detailed presentation and discussion of each of these outcomes, the methodology for measurement, and supporting bibliographic references, see the respective article in this supplement.
        ASS, Asthma Severity Score; cACT, childhood Asthma Control Test; CAS, Clinical Asthma Score; CBC, complete blood count; CHSA, Child Health Survey for Asthma; ED, emergency department; Feno, fractional exhaled nitric oxide; ICU, intensive care unit; LTE4, leukotriene E4; PACD, Pediatric Asthma Caregiver Diary; PAQLQ, Pediatric Asthma Quality of Life Questionnaire; PASS, Pediatric Asthma Severity Score; Pediatric Caregiver AQLQ, Pediatric Caregiver Asthma Quality of Life Questionnaire; PedsQL, Pediatric Quality of Life Inventory; PEF, peak expiratory flow; PI, Pulmonary Index; PRAM, Preschool Respiratory Assessment Measure; PS, Pulmonary Score; SES, socioeconomic status; WPAI, Work Productivity and Activity Impairment Questionnaire.
        Only some of these outcomes are also suitable for children 0 to 4 years of age.
        Observational study designs include cohort, case-control, cross-sectional, retrospective reviews; genome-wide association studies; and secondary analysis of existing data. Some measures may not be available in studies using previously collected data.
        Methacholine inhalation and exercise challenge (children aged 5 to 7 years are less likely to perform well on these tests).
        § Pulmonary diffusing capacity (breath holding is difficult in children aged 5-7 years); arterial blood gases and pulse oximetry.
      • In some instances the subcommittees were unable to identify core outcomes. This reflected either the lack of adequate validation and standardization or the opinion of subcommittee members that the content of an existing tool may not adequately represent the essence of the outcome for which it was developed. In these cases the subcommittees have identified clear needs for the development and validation of new tools.
      • For outcomes and outcome measures that, despite their potential importance, have been designated as emerging because of the lack of adequate validation and standardization, the articles of the workshop report raise specific questions that need to be addressed in future research.
      • Each subcommittee presents suggestions for future directions and research to help guide future projects that could fill existing gaps.

      Additional considerations

       Mediators of asthma outcomes

      The Quality of Life Subcommittee recognized that such factors as patient adherence, level of asthma self-management skills, and exposure to stress can have considerable influence on a wide range of asthma outcomes and not just the patients’ perceptions of the impact of asthma on their quality of life. Although the review of these mediators was beyond the scope of any 1 subcommittee’s topic, the Quality of Life Subcommittee offers a brief summary of these factors and their potential influence to encourage consideration of these issues in a broad range of asthma clinical research. This summary is presented as an additional article in the workshop report.

       Validation studies of questionnaires or interview instruments

      The Composite Scores of Asthma Control, Quality of Life, and Symptoms Subcommittees reviewed the psychometric properties of a variety of instruments identified through their literature searches. These reviews revealed considerable variation in how investigators defined the terms of construct, convergent, and criterion in presenting evidence concerning the validity of their instruments. Therefore it was not possible to expect each subcommittee to use uniform definitions, such as those contained in the standards for educational and psychological testing issued jointly by the American Educational Research Association, American Psychological Association, and National Council on Measurement in Education.
      American Educational Research Association; American Psychological Association; National Council on Measurement in Education
      Standards for educational and psychological testing.
      As noted by the authors, these standards apply not only to measurement instruments commonly considered “tests” but also to scales, inventories, and any other evaluative procedure in which a sample of an examinee’s behavior is obtained and subsequently evaluated and scored using a standardized process. Consequently, each subcommittee’s article contains the definitions used. This issue underscores yet another dimension of standardization that is needed for the development of asthma outcome measures. Developers of future asthma outcome instruments that depend on patient report or performance are encouraged to use these published, widely accepted standards in much the same manner as the asthma community uses the ATS standards for lung function measurements.

       Demographic characterization

      Each article of the workshop report includes a recommendation for the demographic characterization of the study population, noting that such features as age, sex, race or ethnicity, and socioeconomic status may influence measurement or interpretation of outcomes of interest to the subcommittee. However, there is an overarching need for basic demographic characterization of the population to also use standardized definitions. For example, the differentiation of age groups 0 to 4 years, 5 to 11 years, and 12 or more years is common among asthma studies and clinical practice guidelines. However, the Exacerbations Subcommittee notes a need to distinguish adolescents (aged 12-17 years), adults 18 to 64 years old, and adults 65 years and older. It is apparent from the literature reviewed that investigators have used varying categorizations of race and ethnicity, as well as socioeconomic status. Future investigators are encouraged, at a minimum, to report the specific definitions they use, and are further encouraged to use the NIH’s standard definitions of race and ethnicity (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-053.html) and a referenced source for defining socioeconomic status (eg, the proportion of the study population below the poverty level as defined by the US Census Bureau, http://www.census.gov/hhes/www/poverty/methods/definitions.html, or the level of education of study participants or their households).

       Patient-reported outcomes

      The Patient Report Outcomes Measurement System (PROMIS) is a trans-NIH initiative managed by the National Institute of Arthritis and Musculoskeletal and Skin Diseases to develop new, standardized, and psychometrically robust ways to measure patient-reported symptoms, such as pain, fatigue, physical functioning, and aspects of health-related quality of life across a wide variety of chronic diseases and conditions (http://nihroadmap.nih.gov/clinicalresearch/promis). The goal is to develop a set of publicly available computerized adaptive tests for the clinical research community. Researchers will select from a bank of questionnaire items related to different domains (eg, pain and fatigue) to create questionnaires for their respective studies, whether administered through an iterative computer adaptive testing system or paper version short forms. PROMIS is now testing the application of its initial generic domains for use in patients with specific diseases, including asthma. Because this initiative is still in development, the Asthma Outcomes workshop could not conduct a review of PROMIS instruments. However, it is hoped that this brief description will encourage clinical investigators to check the PROMIS Web site for updates that may be helpful for their research.

       Summary

      The enthusiasm with which such a large cross-section of clinical research scientists in asthma worked together to develop proposals for standardizing asthma outcomes reflects the high-level importance of this endeavor. Workshop participants endorsed the conviction that harmonization of asthma outcomes is critical for cross-study comparisons, genome-wide association studies, and data sharing. It is hoped that investigators in the medical and scientific communities will incorporate these workshop proposals into their future research and will undertake research to further enhance asthma outcomes measurement.

      References

        • Akinbami L.J.
        • Moorman J.E.
        • Liu X.
        Asthma prevalence, health care use, and mortality: United States, 2005-2009.
        National Center for Health Statistics, Hyattsville (MD)2011
        • Reddel H.K.
        • Taylor D.R.
        • Bateman E.D.
        • Boulet L.P.
        • Boushey H.A.
        • Busse W.W.
        • et al.
        An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
        Am J Respir Crit Care Med. 2009; 180 (Epub 2009/06/19): 59-99
        • American Educational Research Association; American Psychological Association; National Council on Measurement in Education
        Standards for educational and psychological testing.
        American Educational Research Association, Washington (DC)1999

      Linked Article

      • Sputum cell counts and methacholine hyperresponsiveness as asthma outcomes
        Journal of Allergy and Clinical ImmunologyVol. 130Issue 3
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          The National Institutes of Health and the Agency for Healthcare Research and Quality are to be commended for convening a workshop to make recommendations for inclusion of core and optional measurements as baseline and outcome variables for clinical trials to evaluate various interventions in asthmatic patients.1 However, we would like to point out 2 misinterpretations related to the use of sputum cell counts and methacholine hyperresponsiveness, both of which are considered supplemental and not core measurements.
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