National Academies Press: OpenBook
Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

BioWatch

PCR Assays

Building Confidence,
Ensuring Reliability

Committee on PCR Standards for the BioWatch Program

Board on Life Sciences
Division on Earth and Life Studies

Board on Health Sciences Policy
Institute of Medicine

NATIONAL RESEARCH COUNCIL AND
                     INSTITUTE OF MEDICINE
                                 OF THE NATIONAL ACADEMIES

Abbreviated Version

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

www.nap.edu

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

THE NATIONAL ACADEMIES PRESS    500 Fifth Street, NW    Washington, DC 20001

NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.

This study was supported by Contract No. HSHQDC-11-D-00009/Order No. HSHQDC-13-J-00274 between the National Academy of Sciences and the U.S. Department of Homeland Security. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project.

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Printed in the United States of America.

Suggested citation: NRC (National Research Council) and IOM (Institute of Medicine). 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability. Washington, DC: The National Academies Press.

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

THE NATIONAL ACADEMIES

Advisers to the Nation on Science, Engineering, and Medicine

The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.

The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., is president of the National Academy of Engineering.

The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Victor J. Dzau is president of the Institute of Medicine.

The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.

www.national-academies.org

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
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×

COMMITTEE ON PCR STANDARDS FOR
THE BIOWATCH PROGRAM

GEORGES C. BENJAMIN (Co-Chair), Executive Director, American Public Health Association, Washington, DC

KENNETH I. BERNS (Co-Chair), Distinguished Professor of Molecular Genetics and Microbiology Emeritus, University of Florida College of Medicine, Gainesville

EDWIN P. PRZYBYLOWICZ (Co-Chair), Senior Vice President and Director of Research (retired), Eastman Kodak Company, Webster, NY

BRUCE BUDOWLE, Executive Director, Institute of Applied Genetics, and Professor, Department of Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth

CHARLES CHIU, Associate Professor, Laboratory Medicine and Medicine, Infectious Diseases; Director, UCSF-Abbott Viral Diagnostics and Discovery Center at China Basin; and Associate Director of the UCSF Clinical Microbiology Laboratory, University of California, San Francisco

JOHN M. HARDHAM, Associate Research Fellow and Chair, Emerging Infectious Disease Program, Zoetis, Inc., Kalamazoo, MI

GRACE KUBIN, Director, Laboratory Services Section, Texas Department of State Health Services, Austin

M. ALLEN NORTHRUP, Principal, Northrup Consulting Group, San Francisco, CA

TOM SLEZAK, Program Leader, Global Security Program, E.O. Lawrence Livermore National Laboratory, Livermore, CA

PETER M. VALLONE, Leader, Applied Genetics Group, Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD

Study Staff

KATHERINE BOWMAN, Study Director, Board on Life Sciences

AUTUMN DOWNEY, Program Officer, Board on Health Sciences Policy

KATHRYN HUGHES, Senior Program Officer, Board on Chemical Sciences and Technology

JON Q. SANDERS, Program Coordinator, Board on the Health of Select Populations (until November 2014)

NIA D. JOHNSON, Senior Research Associate, Board on Army Science and Technology (from November 2014 to March 2015)

_________________

Since June 2014.

Until May 2014.

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

CLAIRE BALLWEG, Senior Program Assistant, Board on Environmental Studies and Toxicology (from May 2015)

BETHELHEM MEKASHA, Financial Associate, Board on Life Sciences

ANDREW POPE, Director, Board on Health Sciences Policy

FRANCES SHARPLES, Director, Board on Life Sciences

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

BOARD ON LIFE SCIENCES

JAMES P. COLLINS (Chair), Arizona State University, Tempe

ENRIQUETA C. BOND, Burroughs Wellcome Fund, Marshall, VA

ROGER D. CONE, Vanderbilt University Medical Center, Nashville, TN

JOSEPH R. ECKER, Salk Institute for Biological Studies, LaJolla, CA

SEAN EDDY, HHMI Janelia Farm Research Campus, Ashburn, VA

SARAH C. R. ELGIN, Washington University, St. Louis, MO

DAVID R. FRANZ, Consultant, Frederick, MD

STEPHEN FRIEND, Sage Bionetworks, Seattle, WA

ELIZABETH HEITMAN, Vanderbilt University Medical Center, Nashville, TN

RICHARD A. JOHNSON, Global Helix LLC, Washington, DC

JUDITH KIMBLE, University of Wisconsin, Madison

MARY E. MAXON, Science Philanthropy Alliance, Palo Alto, CA

KAREN E. NELSON, J. Craig Venter Institute, Rockville, MD

ROBERT M. NEREM, Georgia Institute of Technology, Atlanta

MARY E. POWER, University of California, Berkeley

MARGARET RILEY, University of Massachusetts, Amherst

LANA SKIRBOLL, Sanofi, Washington, DC

JANIS C. WEEKS, University of Oregon, Eugene

MARY WOOLLEY, Research!America, Alexandria, VA

Staff

FRANCES E. SHARPLES, Director

JO L. HUSBANDS, Scholar/Senior Project Director

JAY B. LABOV, Senior Scientist/Program Director for Biology Education

LIDA ANESTIDOU, Senior Program Officer, ILAR

KATHERINE W. BOWMAN, Senior Program Officer

MARILEE K. SHELTON-DAVENPORT, Senior Program Officer

KEEGAN SAWYER, Program Officer

AUDREY THEVENON, Associate Program Officer

VANESSA LESTER, Research Associate

BETHELHEM M. MEKASHA, Financial Associate

ANGELA KOLESNIKOVA, Administrative Assistant

JENNA OGILVIE, Senior Program Assistant

KANOKO MAEDA, Senior Program Assistant

Page viii Cite
Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
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BOARD ON HEALTH SCIENCES POLICY

JEFFREY KAHN (Chair), Johns Hopkins University, Baltimore, MD

ELI Y. ADASHI, Brown University, Providence, RI

HUDA AKIL, University of Michigan, Ann Arbor

WYLIE BURKE, University of Washington, Seattle

ROBERT M. CALIFF, Duke University Medical Center, Durham, NC

R. ALTA CHARO, University of Wisconsin, Madison

KATHLEEN A. DRACUP, University of California, San Francisco

MICHAEL EHLERS, Pfizer Inc., Cambridge, MA

NAOMI L. GERBER, George Mason University, Fairfax, VA

LEWIS R. GOLDFRANK, New York University School of Medicine, New York City

STEVEN E. HYMAN, The Broad Institute, Cambridge, MA

PATRICIA A. KING, Georgetown University Law Center, Washington, DC

HARRY T. ORR, University of Minnesota, Minneapolis

SHARON TERRY, Genetic Alliance, Washington, DC

REED V. TUCKSON, Tuckson Health Connections, LLC, Edina, MN

CLYDE YANCY, Northwestern University, Chicago, IL

Staff

ANDREW M. POPE, Director

BRUCE ALTEVOGT, Senior Program Officer

AUTUMN DOWNEY, Program Officer

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

Acknowledgments

This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report:

Cynthia Bruckner-Lea, Pacific Northwest National Laboratory

Nancy D. Connell, Rutgers New Jersey Medical School

Christina Egan, New York State Department of Health

Sean Eddy, Howard Hughes Medical Institute Janelia Farm Research Campus

Joan Gebhardt, Naval Medical Research Center

Jonna A.K. Mazet, University of California, Davis

Suzet M. McKinney, Chicago Department of Public Health

R. Paul Schaudies, GenArraytion, Inc.

Victor Waddell, Arizona Department of Health Services

Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

before its release. The review of this report was overseen by Ronald M. Atlas, University of Louisville and David R. Walt, Tufts University. Appointed by the National Research Council, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

The committee thanks all those who provided information during the course of the study. The committee particularly thanks Kerby Shedden, University of Michigan, and Michael Cohen, National Research Council, for their assistance and thoughtful conversations on statistical confidence intervals and experimental design.

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

Preface

Knowing when a health threat enters a community is the cornerstone of biopreparedness. Historically, public health officials have had to rely on a clinical detection system that includes the astute clinician, the unanticipated lab result, or a cluster of disease cases to know that some disease threat was present. These methods of detection, while important, may put the health security system behind the curve in responding to a disease threat in the case of a bioterrorist attack. The BioWatch program is designed to get upstream of these clinical detection systems by providing early warning to local, state, and federal partners should an airborne release of certain types of biothreat agents occur. The program relies on collectors deployed in jurisdictions around the country, and on sample results provided through public health laboratories. It is a component of a much broader monitoring and surveillance effort to identify and respond to terrorist threats that ensures the health security of the nation.

Ensuring health security requires an early warning system with which its users have a high degree of confidence. The users need a clear understanding of the meaning and limitations of the data they receive and have trust that they can use the results to make subsequent, potentially high-consequence decisions. As the report discusses, standards and validation provide a necessary basis for confidence in the system.

Although standards may not seem glamorous, they are fundamental. Our own experiences studying infectious microorganisms and working to support a strong and effective public health system lent us motivation

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
×

for the task. The committee welcomed the opportunity to bring attention to the critical roles that standards play in supporting a program such as BioWatch, the efforts that have taken place to develop performance standards that could be applicable to program needs, and the base of information that has been gathered on BioWatch assay and system performance. Based on our statement of task, the report focuses on performance standards for the polymerase chain reaction (PCR) assays used in BioWatch, while emphasizing that all of the system’s components are necessarily interconnected. It is evident that the rapid development of next-generation sequencing offers the promise of a more definitive approach to the secondary verification or confirmation step required after the initial PCR assay in order to secure the trust required for responsible public health officials and other government authorities to initiate an appropriate response to a select agent detection.

We were joined in our task by fellow committee members with diverse areas of expertise in genetics and molecular biology, bioinformatics, technology development, and public health. We thank them for their commitment to the study topic and for giving so willingly of their time and energy. It has been a pleasure to work with each of them. The report was also informed by presentations and discussions with a number of experts in environmental biosurveillance, pathogen biology, biodetection, assay and standards development, and validation from within and outside the federal government, as well as from state and local BioWatch jurisdictions. Their contributions were critical in informing the committee and we thank them for their willingness to share their views with us.

Finally, on behalf of the committee, we would like to thank the staff of the National Research Council and the Institute of Medicine for their assistance and dedication in working alongside us. Their support was integral in bringing the project to fruition.

Georges C. Benjamin
Kenneth I. Berns
Co-Chairs

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Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
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Appendix A to the Committee’s report has been determined by the sponsor to contain information described in one or more of the exemptions to the Freedom of Information Act, 5 U.S.C. § 552(b) (FOIA). Section 15 of the Federal Advisory Committee Act provides that the Academy shall make available to the public its final report unless the Academy determines that the report would disclose matters described in Section 552(b). In such case, the Academy “shall make public an abbreviated version of the report that does not disclose those matters.” This abbreviated version of the report includes all of the committee’s findings, recommendations, and other substantive material without disclosing materials described in 5 U.S.C. § 552(b).

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
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3. KEY COMPONENTS OF A PERFORMANCE STANDARD 53 FOR BIOWATCH

Tradeoffs in Performance and Assay Purpose

Assay Sensitivity and Limit of Detection

Assay Specificity: Strain and Substance Panels

Understanding Environmental Background

Microbial Diversity

Assay Precision and Other Performance Parameters

Positive and Negative PCR Assay Controls

Testing Laboratory Setup and Management

Reference Material Availability

Time and Cost Considerations

Use of Prior and Ongoing Performance Test Information

4. THE FRAMEWORK THAT SURROUNDS THE PCR REACTION AFFECTS PERFORMANCE

Sample Collection, Extraction, and Purification Affect PCR Assay Performance

Validation Is the Framework That Supports Quality

Continuous Monitoring and Assessment Is a Necessary Part of Validation

Applying Validation Principles to Assay Performance Characterization: Putting These into Practice

Constraints of the Current System and Operational Experience of BioWatch Jurisdictions

5. LOOKING TO THE FUTURE: MULTIPLEX PCR AND NEXT-GENERATION SEQUENCING

Multiplexing PCR Assays for Use in BioWatch

Taking Account of Step Changes in Technology

6. CONCLUSIONS AND RECOMMENDATIONS

Fundamental Principles of Performance Standards and Validation

Approaches to Assay Performance Characterization and Validation

A Robust Quality Assurance Program Contributes to Confidence in the System but Communication Challenges Remain

Standards Approaches for Multiplexing Real-Time PCR Assays

Incorporating Advances in Sequencing Technology into the Program

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2-1 BioWatch operations include multiple steps. PCR assay performance standards are associated with both the screening and secondary assays, and quality assurance standards are associated with the framework from sampling through output

3-1 Flowchart representing steps in assay analytical performance characterization

3-2 A hypothetical POD curve, as defined by the SPADA validation guidelines, depends on concentration and can be related to other commonly used assay performance concepts

3-3 A. Representation of the Burkholderia pseudomallei pan-genome. B. Effect this has on the selection of DNA signatures that can be used in designing PCR assays

3-4 Laboratory organization used by LANL in conducting assay testing

4-1 PCR assay. Several key steps precede the PCR amplification reaction. When combined with a detection mode, these steps form a complete PCR assay

4-2 PCR assay performance is influenced by feedback from the steps that follow a result and the surrounding QA infrastructure

4-3 Steps in assay and system validation

TABLES

S-1 Applications of Next-Generation Sequencing for BioWatch

1-1 Selected Federal Strategy Documents Related to Environmental Biosurveillance

2-1 Time Line of Selected Programs and Milestones

2-2 Recent BioWatch Performance Testing and Validation Activities

3-1 Comparison of Binomial Confidence Intervals for Varying Numbers of Tests, Calculated Using Several Confidence Interval Methods

3-2 Comparison of SPADA, PHAA/FSAPE, and BioWatch Acquisition Testing Approaches

3-3 Comparison of Two Assay Performance Approaches on Several of the Parameters Discussed in the Report

3-4 Comparison of the Numbers of Inclusivity and Exclusivity Strains for a Representative Sample of Agents Under Different Standards Approaches

Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
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Acronyms and Abbreviations

APHL Association of Public Health Laboratories
   
BAR BioWatch Actionable Result
BDS Post Office Biohazard Detection System
BTRA Biological Terrorism Risk Assessment
   
CBRNE chemical, biological, radiological, nuclear, and explosives
CDC Centers for Disease Control and Prevention
CRP Department of Defense Critical Reagents Program
CRS Congressional Research Service
Ct threshold cycle
   
DHS Department of Homeland Security
DNA deoxyribonucleic acid
DOD Department of Defense
DOJ Department of Justice
DTO Defense Technology Objective
   
EPA Environmental Protection Agency
EUA emergency use authorization
   
FBI Federal Bureau of Investigation
FDA Food and Drug Administration
FSAPE Federal Standards for Assay Performance and Equivalency
   
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GAO Government Accountability Office
   
HHS Department of Health and Human Services
   
IOM Institute of Medicine
   
JPEO-CBD Joint Program Executive Office for Chemical and Biological Defense
   
LANL Los Alamos National Laboratory
LLNL Lawrence Livermore National Laboratory
LOD limit of detection
LRN Laboratory Response Network
   
MFI median fluorescence intensity
MIQE Minimum Information for Publication of Quantitative Real-Time PCR Experiments
MOU memorandum of understanding
   
NAS National Academy of Sciences
NPV negative predictive value
NRC National Research Council
NTTAA National Technology Transfer and Advancement Act
   
OHA DHS Office of Heath Affairs
OIE World Organisation for Animal Health
OMB Office of Management and Budget
   
PCR polymerase chain reaction
PHAA Public Health Actionable Assay
POD probability of detection
PSAA Public Safety Actionable Assay
PPV positive predictive value
   
S&T science and technology
SMPR Standard Method Performance Requirement
SPADA Stakeholder Panel on Agent Detection Assays
   
USAMRIID U.S. Army Medical Research Institute of Infectious Diseases
USPS U.S. Postal Service
Suggested Citation:"Front Matter." Institute of Medicine and National Research Council. 2015. BioWatch PCR Assays: Building Confidence, Ensuring Reliability: Abbreviated Version. Washington, DC: The National Academies Press. doi: 10.17226/21658.
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BioWatch is an air monitoring system deployed in jurisdictions around the country with the goal of detecting the presence of certain high risk pathogenic microorganisms. It relies on a network of federal and nonfederal collaborative relationships to be successful, and is one part of a larger array of disease surveillance, intelligence-gathering, and biomonitoring activities in support of public safety and health. The assays used in the BioWatch system to detect the presence of pathogens in collected samples rely on the technique of polymerase chain reaction (PCR) to sensitively and specifically amplify target nucleic acid sequences.

BioWatch PCR Assays evaluates and provides guidance on appropriate standards for the validation and verification of PCR tests and assays in order to ensure that adequate performance data are available to public health and other key decision makers with a sufficient confidence level to facilitate the public health response to a BioWatch Actionable Response. This report discusses principles of performance standards, reviews information from several existing guidance documents and standards that might be applicable to BioWatch, and discusses assay testing efforts that have occurred or are ongoing. BioWatch PCR Assays provides recommendations on general principles and approaches for a performance standard and validation framework to meet BioWatch's mission. The report also considers how developments in technology, particularly in multiplex PCR and next-generation sequencing, can contribute to the ability of the BioWatch program to meet current and future challenges.

This report has been determined to contain information exempt from disclosure under 5 U.S.C. 552(b). Section 15 of the Federal Advisory Committee Act provides that the National Academies shall make its final report available to the public unless the National Academies determines that the report would disclose matters described in one or more of the exemption provisions under the Freedom of Information Act (FOIA). In such case, the National Academies "shall make public an abbreviated version of the report that does not disclose those matters." This unrestricted, abbreviated version of the report represents, in so far as possible, the committee's findings, recommendations, and other substantive material without disclosing materials described in 5 U.S.C. 552(b).

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