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Draft Genetic Test Review

Cystic Fibrosis
Introduction
Print Version


ACCE Wheel:  Clinical Utility, Clinical Validity, Analytic Validity, Disorder and Setting

ACCE

A CDC Sponsored Project

Population-Based Prenatal Screening for Cystic Fibrosis via Carrier Testing

page 1 | page 2 | page 3


Editors

James E. Haddow, M.D., Glenn E. Palomaki, B.S., B.A.  
Foundation for Blood Research 
Scarborough, Maine 04074

Produced under a cooperative agreement (UR3/CCU319352) with the Centers for Disease Control and Prevention, Office of Genomics and Disease Prevention

The following individuals contributed original material to this report: 

Linda A. Bradley, Ph.D.
Clinigene Laboratories, Hauppauge, New York

Scott Grosse, Ph.D.
Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, Georgia

James E. Haddow, M.D.  
Foundation for Blood Research, Scarborough, Maine  

James B. Haddow, Esq.  
Petruccelli, Martin, & Haddow, LLP, Portland, Maine  

Glenn E. Palomaki, B.A.  
Division of Biometry, Foundation for Blood Research, Scarborough, Maine  

Nancy A. Press, Ph.D.  
Division of Medical Genetics, Oregon Health Sciences University, Portland, Oregon  

Carolyn Sue Richards, Ph.D.  
Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas

This is a public domain document and may be used without explicit consent.  The source should, however, be cited.  A suggested citation might be Haddow JE and Palomaki GE.  Population-based prenatal screening for cystic fibrosis via carrier testing: ACCE review. www.cdc.gov/genomics/info/reports/research/FBR/ACCE.htm

The authors of this report are responsible for its content.  Statement in the report should not be construed as endorsement by the Centers for Disease Control and Prevention.

Members of the ACCE Core Group during the time this report was conceived and executed include:

James E. Haddow, M.D., Principal Investigator
Foundation for Blood Research, Scarborough, Maine

Linda A. Bradley, Ph.D.  
Clinigene Laboratories, Hauppauge, New York  

Marta Gwinn, M.D., M.P.H.  
Division of Genomics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia

Muin J. Khoury, M.D., Ph.D.  
Division of Genomics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia

Glenn E. Palomaki, B.S., B.A.  
Division of Biometry, Foundation for Blood Research, Scarborough, Maine  

Carolyn Sue Richards, Ph.D.  
Dept. of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas  

Paula Yoon, ScD, M.P.H.  
Division of Genomics and Disease Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia 

Reviewers of Population-Based Prenatal Screening for Cystic Fibrosis via Carrier Testing, along with a summary of their comments and responses, are listed at the end of this report (Section 7, Glossary and Comments). 

June 17, 2002

TABLE OF CONTENTS 

PAGE
Introduction to ACCE ...........................................................................................................................  vii
Genetic Test Brief: Population-Based Screening for Cystic
Fibrosis via Carrier Testing ..................................................................................................
 xii
Specific Issues or Gaps in Knowledge that Need to be Addressed...............................................
xvii

DISORDER/SETTING

Question 1:  What is the specific clinical disorder to be studied?..........................................................
Question 2:  What are the clinical findings defining this disorder?..........................................................
Question 3:  What is the clinical setting in which the test is to be performed?........................................
Question 4:  What DNA test(s) are associated with this disorder?.......................................................
Question 5:  Are preliminary screening questions employed?...............................................................
Question 6:  Is it a stand-alone test or is it one of a series of tests?......................................................
Question 7:  If it is part of a series of screening tests, are all tests performed in all instances (parallel) or are some tests performed only on the basis of other results (series)? ......................................................
1-2
1-5
1-6
1-7
1-9
1-10

1-11


ANALYTIC VALIDITY

Question 8:  Is the test qualitative or quantitative?................................................................................
Question 9:  How often is a test positive when a mutation is present?...................................................
Question 10:  How often is the test negative when a mutation is not present?........................................
Question 11:  Is an internal QC program defined and externally monitored?........................................
Question 12:  Have repeated measurements been made on specimens?..............................................
Question 13:  What is the within- and between-laboratory precision?.................................................
Question 14:  If appropriate, how is confirmatory testing performed to resolve false positive results in a timely manner? ...................................................................................................................................
Question 15:  What range of patient specimens has been tested?........................................................
Question 16:  How often does the test fail to give a useable result?....................................................
Question 17:  How similar are results obtained in multiple laboratories using the same, or different technologies?.....................................................................................................................................
2-2
2-9
2-9
2-20
2-23
2-24

2-25
2-28
2-30

2-32


CLINICAL VALIDITY

Question 18:  How often is the test positive when the disorder is present?............................................ 
Question 19:  How often is the test negative when the disorder is not present?....................................
Question 20:  Are there methods to resolve clinical false positive results in a timely manner?................
Question 21:  What is the prevalence of the disorder in this setting? ...................................................
Question 22:  Has the test been adequately validated on all populations to which it may be offered? ...
Question 23:  What are the positive and negative predictive values?....................................................
Question 24:  What are the genotype/phenotype relationships?...........................................................
Question 25:  What are the genetic, environmental or other modifiers?................................................
3-2
3-2
3-35
3-27
3-70
3-71
3-83
3-90

CLINICAL UTILITY

Question 26:  What is the natural history of the disorder?....................................................................
Question 27:  What is the impact of a positive (or negative) test on patient care?..................................
Question 28:  If applicable, are diagnostic tests available?...................................................................
Question 29:  Is there an effective remedy or acceptable action, or other measurable benefit?..............
Question 30:  Is there general access to that remedy or action?...........................................................
Question 31:  Is the test being offered to a socially vulnerable population?..........................................
Question 32:  What quality assurance measures are in place?.............................................................
Question 33:  What are the results of pilot trials?................................................................................
Question 34:  What health risks can be identified for follow-up testing and/or intervention?..................
Question 35:  What are the financial costs associated with testing?......................................................
Question 36:  What are the economic benefits associated with actions resulting from testing?...............
Question 37:  What facilities/personnel are available or easily put in place?.........................................
Question 38:  What educational materials have been developed and validated, and which of these are available?...........................................................................................................................................
Question 39:  Are there informed consent requirements?.....................................................................
Question 40:  What methods exist for long term monitoring?...............................................................
Question 41:  What guidelines have been developed for evaluating program performance?................
4-2
4-5
4-7
4-8
4-9
4-10
4-11
4-18
4-26
4-33
4-36
4-69

4-72
4-79
4-80
4-85


ELSI

Question 42:  What is known about stigmatization, discrimination, privacy/confidentiality and personal/family social issues?..............................................................................................................
Question 43:  Are there legal issues regarding consent, ownership of data and/or samples, patents, licensing, proprietary testing, obligation to disclose or reporting requirements?.....................................
Question 44:  What safeguards have been described and are these safeguards in place and effective?....................................................................................................................
 
5-2

5-4


Master List of References...............................................................................................................
Genetic Testing Glossary.................................................................................................................
List of Reviewers.............................................................................................................................
6-2
6-9
6-21

 

Updated on August 13, 2004