Cystic Fibrosis and DNA Tests:

Implications of Carrier Screening

August 1992

OTA-BA-532

NTIS order #PB92-216142

GPO stock #052-003-01291-0
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Cystic Fibrosis and DNA Tests:

Implications of Carrier Screening, OTA-BA-532 (Washington, DC: U.S. Government

Printing Office, August 1992).
Foreword

Nearly 10 years ago, the President’s Commission for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research speculated about the potential ethical,

legal, and social consequences that might occur if a test were available to identify carriers for

cystic fibrosis (CF)l

, the most common, life-shortening, recessive genetic disease in American

Caucasians. Time and technology have moved forward. The mysteries of biological

inheritance-first explored by Austrian monk Gregor Mendel over a century ago-are

yielding to modern science. A CF carrier test is no longer a prospect; it is now reality. The

test’s existence raises broad societal questions about the use of genetic information. And

beyond CF tests, expectations of scores of additional genetic tests loom on the horizon as

scientists in the United States and abroad pursue an ambitious mission to map and sequence

the entire human genetic blueprint, or genome.

Ongoing interest in the Human Genome Project, as well as concern about the potential

magnitude and effects of routine CF carrier screening, led the House Committee on Science,

Space, and Technology and the House Committee on Energy and Commerce to request an

evaluation of the scientific, clinical, legal, economic, and social considerations of widespread

carrier screening for CF. The study was also endorsed by Representative David R. Obey.

Cystic Fibrosis and DNA Tests: Implications of Carrier Screening presents a range of options

for action by the U.S. Congress in six broad policy areas:

● genetics education and the public,

● gentics training and education of health care professionals,

● disc rumination,

. clinical laboratory and medical device regulation,

● instrumentation to automate DNA diagnostics, and

● integration of DNA assays into routine clinical practice.

OTA prepared this report with the assistance of a panel of advisors and reviewers selected

for their expertise and diverse points of view. Additionally, hundreds of individuals

cooperated with OTA staff through interviews or by providing written material. These

authorities were drawn from academia, industry, and professional societies, as well as Federal

and State agencies. OTA gratefully acknowledges the contribution of each of these

individuals. As with all OTA reports, however, responsibility for the content is OTA’s alone.

In publishing this report, OTA concludes that the value of the CF carrier test is the

information it provides. No one can estimate in common terms what it means to an individual

to possess information about his or her genetic status, especially when the value concerns

reproductive decisionmaking. As our knowledge of the human genome increases, what we do

with information such as CF carrier status will depend on the perceptions and beliefs of all

Americans. We believe that public understanding of this new knowledge and its implications

is necessary for its wise and thoughtful application.

| JOHN H.-GIBBONS

 Directo r

l~e~ldent’~ Cobsslon for tie Smdy of E~c~ ~oblems fi Me&cke and Biomdical and Behavioral Research, ~CMt?t@

and Counseling for Genetic Conditions: The Ethical, Social, and Lqal Implications of Genetic Screening, Counseling, and

Education Programs (Washington DC: U.S. Government Printing Office, 1983).

. . .

Ill
Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Advisory Panel

Jessica G. Davis, Panel Chair

Co-Director, Division of Human Genetics

New York Hospital

Cornell University Medical College

New York, NY

Arthur L. Beaudet

Professor

Howard Hughes Medical Institute

Baylor College of Medicine

Houston, TX

Debra L. Collins

Genetic Counselor

University of Kansas Medical Center

Kansas City, KS

Beth A. Fine

Genetic Counselor/Clinical Instructor

Northwestern University Medical School

Chicago, IL

Lynn D. Fleisher

Attorney

Sidley & Austin

Chicago, IL

Clark C. Havighurst

William Neal Reynolds Professor of Law

Duke University School of Law

Durham, NC

John Z. Jacoby, III

Clinical Assistant

The Cystic Fibrosis Center

St. Vincent’s Hospital and Medical Center

New York, NY

Angele Khachadour

General Counsel

Hastings College of the Law

San Francisco, CA

Katherine W. Klinger

Vice President, Science

Integrated Genetics

Framingham, MA

Arthur Lifson

Vice President

CIGNA Companies

Hartford, CT

Robert F. Murray, Jr.

Professor

Department of Pediatrics and Child Health

Howard University School of Medicine

Washington, DC

Mark V. Pauly

Executive Director

Leonard Davis Institute of Health Economics

University of Pennsylvania

Philadelphia, PA

Susan Poling

Parent

Silver Spring, MD

Thomas K. Reed, Jr.

chairman

Vivigen, Inc.

Santa Fe, NM

Philip R. Reilly

President

Shriver Center for Mental Retardation, Inc.

Waltham, MA

Joseph D. Schulman

Director

Genetics & IVF Institute

Fairfax, VA

NOTE: OTA is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel members. The panel does

not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility for the report and the

accuracy of its contents.

iv
Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

OTA Project Staff

Roger C. Herdman, Assistant Director, OTA Health and Life Sciences Division

Michael Gough, Biological Applications Program Manager

Robyn Y. Nishimi, Project Director

Kathi E. Hanna, Senior Analyst

Margaret A. Anderson, Analyst1l and Contractor

Sheryl M. Winston, Research Analyst

Ellen L. Goode, Research Assistant

Claire L. Pouncey, Research Analyst2

Alyson Giardini, Intern3

Administrative Staff

Cécile Parker, Office Administrator

Linda Ray ford-Journiette, Administrative Secretary

Jene Lewis, Secretary

Contractors

Gary B. Ellis, Editor, Silver Spring, MD

Adrienne Asch, New York, NY

John M. Boyle, Schulrnan, Ronca & Bucuvalas, Inc., Silver spring, MD

Ferdinand J. Chabot, Newton, IA

R. Alta Charo, University of Wisconsin, Madison, WI

Jeffrey L. Fox, Washington, DC

Bob Jones, IV, Arlington, VA

F. John Meaney, Scottsdale, AZ

Thomas H. Murray, Case Western Reserve University, Cleveland, OH

Mark V. Pauly, Leonard Davis Institute of Health Economics, Philadelphia, PA

Susan Sanford, MedSciArtCo, Washington, DC

Andrew M. Shorr, Charlottesville, VA

Ann C.M. Smith, Reston, VA

Bonnie Steinbeck, University of Albany, Albany, NY

Janet Weiner, American College of Physicians, Philadelphia, PA

1 ~ough December 1991

2 Through May 1991

3 September - December 1991
Contents

Page

Chapter 1. Summary, Policy Issues, and Congressional Options . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 3. Medical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 4. The State-of-the-Art in Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 5. Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 6. Education and Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 7. Financing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 8. Discrirnination Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 9. Costs and Cost-Effectiveness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 10. Cystic Fibrosis Carrier Screeningin the United Kingdom . . . . . . . . . . . . . . . . . . . .

Appendix A. Epidemiology of Mutations for Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix B, Case Studies of Other Carrier Screening Programs . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix C. Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix D. List of Contractor Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix E. List of Workshops and Participants.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix F. Acronyms and Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

49

69

85

111

141

169

189

213

231

247

254

271

275

276

277

285
Chapter 1

Summary, Policy Issues, and

Congressional Options
Contents

Page

WHAT IS CYSTIC FIBROSIS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

WHY IS CYSTIC FIBROSIS CARRIER SCREENING CONTROVERSIAL? . . . . . . . . . . . . . . 11

WHAT FACTORS WILL AFFECT UTILIZATION? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

WHAT 1S THE ROLE OF CONGRESS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

PROSPECTS FOR THE FUTURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Boxes

l-A. Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

l-B. The Human Genome Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

l-C. Cystic Fibrosis Therapies on the Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

l-D. The Gene Product: The Cystic Fibrosis Transmembrane Conductance Regulator . . . . . . . 9

l-E. Cystic Fibrosis Carrier Tests and Detection Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

l-F. Cystic Fibrosis Carrier Screening in the United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

l-G. Federally Funded Cystic Fibrosis Carrier Screening Pilot Projects . . . . . . . . . . . . . . . . . . . . . 18

l-H. Genetic Services: Federal-State Partnership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

l-I. Bree Walker Lampley and Preventing Versus Allowing Genetic Disability . . . . . . . . . . . . . . 29

Figures

l-1. Median Survival of U. S. Cystic Fibrosis Patients Over Time . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1-2. Age Distribution of U.S. Cystic Fibrosis Patients in 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

l-3. The Structure of DNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1-4. Human Chromosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1-5. The Cystic Fibrosis Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 8

1-6. Occurrence of AF508 Mutation in Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1-7. Techniques for DNA Analysis of Cystic Fibrosis Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1-8. Cystic Fibrosis Mutation Test Results at 85 Percent Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . 13

1-9. Cystic Fibrosis Carrier Screening, 1989-92, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

1-10. Genetic Conditions as Preexisting Conditions: Health Insurers’ Attitudes . . . . . . . . . . . . . 31

1-11. Carrier Status as a Preexisting Condition: Health Insurers’ Attitudes . . . . . . . . . . . . . . . . . . 31

1-12. Genetic Information as Medical Information: Health Insurers’ Attitudes . . . . . . . . . . . . . . 31

1-13. Genetics and the Americans With Disabilities Act of 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Tables

l-1. Incidence of Cystic Fibrosis Among Live Births in the United States . . . . . . . . . . . . . . . . . . 5

1-2. Test Sensitivity and Risk of Child With Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

1-3. Privately Funded Cystic Fibrosis Carrier Screening Pilot Projects . . . . . . . . . . . . . . . . . . . . . . 19

1-4. Medicaid Reimbursement for Genetic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

1-5. Projected Use of Genetic Information by Insurers in 5 and 10 Years , . . . . . . . . . . . . . . . . . . 32

1-6. Case Descriptions of Genetic Testing and Health Insurance Problems . . . . . . . . . . . . . . . . . . 34

1-7. Annual Cost of Medical Care for Cystic Fibrosis Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

1-8. Costs for Cystic Fibrosis Carrier Tests at Selected Facilities . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Chapter 1

Summary, Policy Issues, and Congressional Options

Seeking to learn what the future holds is an

enduring human quality. What will happen? When

will it happen? How will it happen? People have

always pondered such questions about their health

and that of their families. Folk ways once enjoyed

wide favor in medicine, but over the years technology has increasingly eclipsed such methods of

divination. Today, medical technology includes

genetic tools that can deliver predictive information

with ever-increasing accuracy. This report is about

one of those tools: a test that can tell people about

their potential to pass to their offspring a genetic

condition called cystic fibrosis (CF). Some people

want and seek this information; others do not.

CF is the most common, life-shortening, recessive

disorder affecting Caucasians of European descent.

Between 1,700 and 2,000 babies with CF are born

annually in the United States. As in many genetic

conditions, the diagnosis of an infant with CF often

reveals the first clue that the genetic trait exists in the

family. In fact, four of five individuals with CF are

born to families with no previous history of the

illness. In such cases, the parents-as well as their

siblings, parents, and other relatives--do not have

CF. These individuals, referred to as CF carriers,

have no symptoms of CF and might not even have

heard of the condition.

In 1989, scientists identified the most common

change, or mutation, in the genetic material, deoxyribonucleic acid (DNA), that causes CF. Hard on the

heels of this discovery, scientists developed tests to

detect mutations in the area of DNA—the CF

gene—that is responsible for the disease. This report

focuses on using these DNA tests to screen and

identify CF carriers before they have a child with CF

(box l-A). Beyond the approximately 30,000 Americans who have CF, as many as 8 million individuals

could be CF carriers. The report concentrates on

these millions of CF carriers, who are, today, largely

unidentified.

Concern about the scientific, legal, economic,

ethical, and social implications of the prospect that

o Carrier parents

o

Photo credit: Office of Technology Assessment, 1992

Inheritance of cystic fibrosis.

large numbers of people might be screened for their

CF carrier status led the House Committee on

Science, Space, and Technology and the House

Committee on Energy and Commerce to request,

and Representative David R. Obey to endorse, this

Office of Technology Assessment (OTA) report.l

CF carrier screening also commands the attention of

Congress because of Congress’ interest in the

Human Genome Project (box l-B).

WHAT IS CYSTIC FIBROSIS?

CF is not a new disease, First described in 17th

century folklore, medical literature has long documented that CF compromises many functions throughout the body-chiefly the sweat glands and the

respiratory, gastrointestinal, and reproductive systems. It occurs in all racial and ethnic groups,

although more frequently in some than in others

(table l-l). In fiscal year 1991, public and private

] Specific analysis of s~~criil lopics rela(cd to CF canricr scrccmng have been assessed in previous OTA reports, including: newborn screening for

CT; genetic monitoring and scrccning in the workplace; the Human Genome Project; the commercial development of Iests for human genetic disorders;

safety and cfticacy of ,ammoccntes!s, prenatal care, and prcgnanc} mimiigcmcnt; and reproductive technologies and assis[ed conception.

-3-
4 ● cystic Fibrosis and DNA Tests: implications of Carrier Screening

Box l-A—Terminology

OTA defines genetic testing as the use of specific assays to determine the genetic status of individuals already

suspected to be at high risk for a particular inherited condition. While any individual can be considered “at high risk”

for a particular unknown trait, and hence be “tested,” “ at high risk” in this report denotes the presence of a family

history or clinical symptoms. The terms genetic test, genetic assay, and genetic analysis are used interchangeably to

mean the actual laboratory examination of samples.

Genetic screening usually uses the same assays employed for genetic testing, but it is distinguished from genetic

testing by its target population. OTA uses the term “screening” selectively. In this report, it refers to analyzing samples

from individuals without a family history of the disorder, groups of these individuals, or populations. Carrier screening

for CF (or CF carrier screening), then, involves performing tests on persons for whom no family history of the disorder

exists to determine whether they have one normal and one aberrant copy of the CF gene, but not the disorder (which

results horn having two aberrant CF genes).*

Many individuals are CF carriers but do not have a positive family history. In fact, 80 percent of babies born with

CF each year are cases where there was no known family history for CF. Thus, a person contemplating procreation could

inquire about the availability of an assay to determine the probability that he or she could have a child affected with CF.

If there are no relatives with the disorder, the individual could be informed that a test would provide information about

his or her genetic status for CF. The person could then elect to be screened to determine whether he or she is a carrier

for CF. If, however, there is a family history of the disease, a practitioner would ideally inform the individual and his

or her partner about CF carrier assays and they might choose to be tested to determine if they are both carriers.

Genetic counseling is a clinical service that includes providing an individual (and sometimes his or her family) with

information about heritable conditions and their risks. When centered around genetic testing or screening, it involves

both education and psychological counseling to convey information about the ramifications of possible test outcomes,

prepare the client for possible positive or negative analyses, and discuss the implications of the actual test results. Many

types of health professionals perform genetic counseling. OTA reserves the term genetic counselor specifically for

master’ s-level individuals to clarify the legal distinctions in licensing and third-party reimbursement among the different

types of practitioners. But, OTA uses the term genetic counseling generically to refer to the educational and informational

process performed by genetic specialists, including physicians, Ph.D. clinical geneticists, genetic counselors, nurses, and

social workers.

OTA avoids using the term “program” in discussing CF carrier screening in the United States. For some, the term

conotes a formal public health effort led or sanctioned by Federal, State, or local governments. In analyzing CF carrier

screening, OTA’s premise is only that large numbers of Americans could---or will-be screened for their CF carrier

status. OTA remains neutral on whether the assays will be a component of a fixed, regulated scheme or another facet

of general medical practice.

*In contrast, OTA uses the term CF screening (or screening for CT), to mean screening individuals to diagnose the presence or absence

of the actual disorder, in the absence of medical indications of the disease or a family history of CF. This type of diagnostic screening usually

involves newborns, but is rarely done for CF exeept in Colorado and Wisconsin. CF testing of newborns is common if a family history of the

condition exists.

SOURCE: Office of Technology Assessment, 1992.

institutions spent more than $55 million studying childhood ailments often share symptoms with CF,

medical and genetic aspects of CF. This section

provides a brief overview of what this-and past—

research has revealed, providing context for the

policy aspects of CF carrier screening that follow.

Pathology, Diagnosis, and Prognosis

Many affected babies are not immediately diagnosed as having CF. Although the disease is always

present at birth in affected individuals, the onset of

recognizable clinical symptoms varies widely; about

10 percent of cases show symptoms at birth. Other

which contributes to diagnostic difficulties. In

general, most diagnoses occur by age 3.

Physicians diagnose CF using a combination of

clinical criteria and diagnostic laboratory testing.

Although the sweat test remains the primary diagnostic test for CF, DNA mutation analysis can

diagnose over 70 percent of cases, complementing

and Confirming sweat test results in some instances.

CF exerts its greatest toll on the respiratory and

digestive systems, and the severity of respiratory

problems often determines quality of life and length
Chapter l-Summary, Policy Issues, and Congressional Options ● 5

Box l-B—The Human Genome Project

As the 21st century approaches, Congress and the executive branch have made a commitment to determine the

location on the DNA—as has been done for CF-of all other genes in the human body, i.e., to map the human

genome. The Human Genome Project is estimated to be a 15-year, $3-billion project. It has been undertaken with

the expectation that enhanced knowledge about genetic disorders, increased understanding of gene-environment

interactions, and improved genetic diagnoses can advance therapies for the 4,000 or so currently recognized human

genetic conditions; a premise supported by the fact that even prior to launching the Human Genome Project,

advances in medical genetics have directed the development of new treatment strategies and incrementally

improved the management of some genetic conditions.

To address gaps in knowledge about the ethical, legal, and social implications, and perhaps forecast such

consequences of this undertaking, the National Institutes of Health (NIH) and the Department of Energy (DOE) each

fund an Ethical, Legal, and Social Issues (ELSI) program. Funds for each agency’s ELSI effort derive from a set

aside of 3 to 5 percent of appropriations for the total genome initiative budget. In fiscal year 1991, DOE’s ELSI

spending was $1.44 million (3 percent). Fiscal year 1992 spending is targeted at $1.77 million (3 percent).

NIH-ELSI spending for fiscal years 1990 and 1991 has been $1,558,913 (2.6 percent) and $4,037,683 (4.9 percent),

respectively. For fiscal year 1992, NIH-ELSI aims to spend 5 percent of its human genome appropriation. Several

grants supported by NIH/DOE ELSI relate to factors affecting CF carrier screening.

SOURCE: Office of Technology Assessment, 1992.

of survival. Individuals with CF produce thick, There is no cure for CF. Treatment focuses on

sticky mucus. Chronic obstruction and infection of

the airways characterize respiratory difficulties and

result in lung damage that leads to pulmonary and

heart failure. Digestive problems are also common

and often predominate over respiratory symptoms

early in life. Poor nutrition and impaired growth

result because food—particularly fat and protein—

is not broken down and absorbed properly.

Table I-l—Incidence of Cystic Fibrosis Among

Live Births in the United States

managing the respiratory and digestive symptoms to

maintain a stable condition and lengthen lifespan.

Again, because of CF’s varied progression, the

regimen and level of therapy depend on the individual. Most therapy involves home treatment (e.g.,

chest physical therapy to clear mucus from the

lungs), outpatient care at one of more than 110

clinics devoted specifically to CF health care, and

occasional hospital stays. Today, physicians can

look to an ever-expanding array of new pharmaceutical options to manage the care of CF patients; on

the horizon are hopes for gene therapy (box l-C).

Population Incidence (births)

Caucasian. . . . . . . . . . . . . . . . . . . 1 in 2,500abc

Hispanic. . . . . . . . . . . . . . . . . . . . . 1 in 9,600d

African American. . . . . . . . . . . . . . 1 in 17,000a’e to 1 in 19,0001

Asian American. . . . . . . . . . . . . . . 1 in 90,000’

aT. F, Boat, M ,J, Welsh, and A.L. Beaudet, “Cyst Ic Fibrosis, ” The Mefa~liC

Basis of /nherited Disease, CR. Scriver, A.L. Beaudet, W.S. Sly, et al.

(ads.) (New York, NY: McGraw Hill, 1989).

bK.B. Hammond, S.H. Abman, R.J. Sokol, et al., “Efficacy of Statewide

Neonatal Screening for Cystic Fibrosis by Assay of Trypsinogen Concentrations,” New England Journal of Medicine 325:769-774, 1991.

%Y. K. Lemna, G.L. Feldman, B.-S. Kerem, et al., “Mutation Analysis for

Heterozygote Detection and the Prenatal Diagnosis of Cystic Fibrosis,”

New England Journa/of A4ed/cme 322:291-296, 1990,

ds.c, Fltzslmmons, remarks at Fifth Annual Nort hAmerican Cystic Fibrosis

Conference, Dallas, TX, Cctober 1991.

eJ,c. Cunningham and t-,fd. Tauss[g, A Gu/de to Cystic Fibrosis fOr parents

and Children, (Bethesda, MD: Cystic Fibrosis Foundation, 1989).

fl, MacLusky, F,J, M&augtllin, and H.R, Levlnson, “Cystic Fibrosis: part 1,“

Current Prob/erns In Pediatrics, J, D. Lockhart (cd.) (Chicago, IL: Year Book

Medical Publishers, 1985),

SOURCE: Off Ice of Technology Assessment, 1992.

Over the last half-century, treatment of CF has

evolved so that an illness nearly always fatal in early

childhood is now one where life expectancy into

adulthood is common. Fifty years ago, most infants

born with CF died in the first two years of life. In

1990, median survival was 28 years (figure l-l)--

i.e., of the individuals born with CF in 1962, half

were alive in 1990. According to the Cystic Fibrosis

Foundation and others, the life expectancy of an

infant born with CF in 1992 cannot be estimated, but

a few individuals speculate such survival might be

40 years. On the other hand, data from Canada show

the steady increase in lifespan since 1940 has

plateaued in the last decade. Currently, the median

age of an individual with CF in the United States is

12.6 years (figure 1-2).
6 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box l-C-Cystic Fibrosis Therapies on the Horizon

In the last several years, scientists have dramatically increased their comprehension of the intricate cascade of

processes that ultimately destroy the airways and lead to death in people with CF. With greater knowledge comes targeted

strategies to fight the condition. Established CF pulmonary treatments of the past few decades concentrated on fighting

infection and clearing airway mucus. Today, new therapies for CF focus on many facets of ameliorating the disease.

Some treatments aim to prevent infection and subsequent inflammation altogether. These therapies attempt to intervene

at specific junctures in the disease process by decreasing the viscosity of lung secretions, protecting the airway from

destruction and preventing infection, or correcting the ionic imbalance.

Two substances-DNase and amiloride-thin CF lung secretions, each through a different mechanism. Both are

in clinical trials for approval by the U.S. Food and Drug Administration (FDA). Administration of adenosine

triphosphate and uridine triphosphate in conjunction with the diuretic amiloride stimulates choride ion secretion, which

is faulty in people with CF; clinical studies also are being carried out for this therapy.

Ironically, the body’s natural infection-fighting defense mechanism contributes to the destruction of airways in

individuals with CF. Clinical trials are also under way for substances known as antiproteases-including

alpha- 1-antitrypsin, secretory leukocyte protease inhibitor, and a compound known as ICI 200,880. Antiproteases can

protect the airway epitheliums from injury mediated by the body’s natural bacteria-fighting substances. Finally, although

still in the early research stages, recent in vitro evidence demonstrates that cyclic-AMP-stimulating drugs can positively

affect chloride balance in some cells from CF patients, suggesting a future avenue for pharmaceutical intervention.

Gene therapy holds the promise of overcoming the condition, perhaps permanently. Unlike treatments that attack

symptoms of CF, gene therapy focuses on directly altering DNA to rectify deficits of the disease. In theory, new DNA

can be inserted into faulty cells to compensate for the genetic defect. Currently, gene therapy for CF is in the animal

experiment stage. Using a crippled virus, the normal human CF gene has been administered directly to the lungs of rats

by aerosol spray. Scientists demonstrated this DNA was functional 6 weeks after transfer to the rat lungs—i.e., the

genetically engineered DNA was producing normal, human CF gene product. Aerosolized liposomes, fatty capsules that

can transport drugs directly into cells, have been used to deliver alpha- 1-antitrypsin genes into rabbit lungs, and a similar

mechanism might be used to deliver the CF gene to human lungs. Despite significant experimental progress, hurdles

remain for gene therapy for CF to be feasible in humans. Long-term safety of the procedure will need to be demonstrated,

as will the most appropriate means of transferring the gene and duration of treatment.

SOURCE: Office of Technology Assessment, 1992.

Figure l-l—Median Survival of U.S. Cystic Fibrosis

Patients Over Time “

1990

/

28

1980

19

1972

16

/

1966

10.6

As with any chronic illness, individuals with CF

experience emotional and social strains beyond the

physical tolls of the disorder. Children, adolescents,

and adults with CF react differently to the condition.

For the family of a child with CF, the disease can

dominate family activities, particularly if daily

therapy is necessary, as is often the case. But while

the emotional burden of CF can be difficult, many

individuals and their families lead happy, satisfying

lives.

The Cystic Fibrosis Gene

CF is a genetic illness transmitted from parents to

their children via genetic instructions stored in DNA

(figure 1-3). In humans, DNA stores these directions, including those responsible for CF, in genes

arrayed on 46 structures called chromosomes (figure

1-4). The gene responsible for CF lies on chromosome 7.
Chapter l--Sumrnury, Policy Issues, and Congressional Options . 7

Figure 1-2—Age Distribution of U.S. Cystic Fibrosis

Patients in 1990

I

I I I I

o 1 2 3 4 5

Number of persons (thousands)

SOURCE: Office of Technology Assessment, 1992, based on S.C. FitzSimmons, “Cystic Fibrosis Patient Registry, 1990: Annual Data

Report,” Cystic Fibrosis Foundation, Bethesda, MD, January

1992.

●

✎

Figure 1-4—Human

Figure 1-3—The Structure of DNA

SOURCE: Office of Technology Assessment, 1992.

Chromosomes

● ✎ ✍✍

DNA is associated with protein in organized microscopic bundles called chromosomes. Humans have 46

chromosomes: 1 pair of sex chromosomes (two X chromosomes for females; an X and a Y for males) and 22

pairs of autosomes. In 1986, scientists localized the CF gene specifically to chromosome 7.

SOURCE: Vivigen, Inc., Santa Fe, NM, 1992.
8 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Since the 1940s, geneticists have known that CF’s is sufficient to maintain normal physiologic funcpattern of inheritance typifies a recessive condition. tions. A child is born with CF when he or she inherits

For recessive disorders like CF, parents display no the mutant CF gene from each parent---i.e., the child

symptoms of the disorder, but are asymptomatic has two chromosome 7s with one CF mutation on

carriers. All individuals have two chromosome 7s, each.

but for CF, a carrier mother or father has one

chromosome 7 with a CF mutation and one without. The CF gene is distributed over 250,000 contiguThe single copy of the nonmutant CF gene in carriers ous base pairs on chromosome 7 (figure 1-5).

Figure 1-5—The Cystic Fibrosis Gene

Chromosome 7

cell

Cystic fibrosis

transmembrane

conductance

regulator (CFTR)

The CF gene is located on the long arm of chromosome 7, where it is spread over 250,000 base pairs (250 kb) of DNA. Coding regions

of the DNA, or exons, are separated by noncoding regions, or introns. After the DNA is transcribed into messenger RNA (mRNA) comprised

of all 27 exons of the gene, the mRNA is exported from the cell nucleus. Finally, instructions in the mRNA are translated, using special

structures in the cell to assemble 1,480 amino acids into the final protein product.

SOURCE: Office of Technology Assessment, 1992, based on M.C. Iannuzzi and F.S. Collins, “Reverse Genetics and Cystic Fibrosis,” American Journa/ of

Respiratory Cellular and Molecular Biology 2:309-316, 1990.
Chapter 1-Summary, Policy Issues, and Congressional Options ● 9

Box I-D—The Gene Product: The Cystic Fibrosis Transmembrane Conductance Regulator

Cells cannot pump water, but must move fluids across their membranes through a process called osmosis.

Osmosis depends largely on ion movement through pores in the membrane (channels) or through transport systems

designed to convey ions from one side of the membrane to the other. In individuals with CF, regulation of a

particular type of ion transport (chloride; Cl-) is defective.

The product of the CF gene, a protein called the cystic fibrosis transmembrane conductance regulator (CFTR),

mediates Cl- ion flow across membranes. Current evidence suggests that CFTR functions as a channel for Cl- ions.

When the gene carries a AF508 or other mutation, it produces a defective CFTR, which in turn disrupts ion flow

and results in the physiological effects distinctive of CF (e.g., skin with a salty taste and thick mucus). As the

workings of CFTR are clarified, new possibilities for treatment arise.

Conceivably, elucidation of the structure and function of CFTR could facilitate assaying CF carrier status

without using DNA analysis. Such assays theoretically could offer an immediate advantage over DNA-based tests.

Currently, more than 170 different CF mutations exist, and hence more than 170 assays are necessary to detect them.

A functional test could measure the presence of normal or altered CFTR to distinguish unaffected, carrier, or affected

individuals. One test might be able to detect the defective CFTR protein no matter which of the 170+ mutations the

individual had.

Despite expectations that a functional CFTR test could obviate the need for DNA-based CF carrier tests (and

eliminate uncertainty for individuals whose tests are negative), one does not appear imminent. While research to

understand CFTI continues to advance rapidly, some of the results appear to cloud, not clarify, the future of a

functional test to identify CF carriers. CFTR activity differs depending on the cell type and methods used to measure

its activity. In vitro activity also does not correlate with prognosis. Depending on the mutation, a gradient of activity

exists; some mutated CFTRs still exhibit activity, while others show none. This variability would make black and

white interpretation of a functional assay impossible, and perhaps less informative than DNA analyses.

SOURCE: Office of Technology Assessment, 1992.

Scientists know, however, that not all of these bases variation. Most of the other 170+ mutations appear

get translated into the ultimate CF gene product,

called the cystic fibrosis transmembrane conductance regulator (CFTR) (box l-D). What is also

known is CF’s pathology stems from a faulty CFTR,

and that in most people with CF a three-base pair

deletion in each of their CF alleles results in the

flawed CITRs. This three-base pair mutation occurs

at position number 508 in the CFTR (abbreviated as

delta F508 (DF508)). More than 170 additional

mutations in the CF gene also lead to faulty CFTRs.

Individuals with CF have two of the same, or two

different, mutations.

About 70 percent of CF carriers have the DF508

mutation. 2 International studies demonstrate ethnic

and regional variation in the frequency distribution

of this mutation (figure 1-6); as expected, the

multicultural nature of the United States reflects this

in a small fraction of individuals or families,

although a few occur at a frequency as great as 1 to

3 percent.

Predicting the precise clinical course of CF—mild

versus severe-cannot be done from knowing which

mutations are present. Some symptoms (or their lack

of severity), however, correlate with particular

mutations. Digestive difficulties from pancreatic

insufficiency, for example, generally associate with

DF508.

Cystic Fibrosis Mutation Analysis

With localization of the CF gene, DF508, and

other CF mutations, it is now possible to directly

analyze DNA from any individual for the presence

of CF mutations (figure 1-7). Using today’s technologies, CF mutation analysis is usually a one-time

2 Quoted ~utatlon fiquencies for &508 ad other ~ mutations always depend on racial and ethnic &&grOmd. ~OU@OUt this R3port, OTA

presents cment expert estimates of appropriate ranges of detection frequencies or sometimes uses a specific figure with qualification (e.g., about 90

percent; approximately 95 percent). OTA adopts such language to avoid restating each time that a frequency depends on racial and ethnic background,

not to underemphasize the importance in the distribution variation of CF mutations. In some case-made clear within the text—a spcciilc frequency

is chosen for illustrative or hypothetical purposes.
10 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 1 -6—Occurrence of DF508 Mutation in Europe

46

SOURCE: European Working Group on Cystic Fibrosis Genetics, “Gradient of Distribution in Europe of the Major CF

Mutation and of Its Associated Haplotype,” Human Genetics 85:436-445, 1990.

test that can inform an individual whether he or she

carries a CF mutation. Carrier screening for CF (or

CF carrier screening) refers to performing CF

mutation analysis on DNA from an individual who

has no family history of CF.

Current technology, however, can leave ambiguity, but not because the tests per se are imprecise.

Properly performed, DNA-based tests for CF mutations are accurate and specific-meaning if the

DF508 mutation (or another CF mutation for which

the test is run) is present in the individual’s genome,

the assay detects it more than 99 percent of the time,

absent laboratory error. Instead, ambiguity stems

from the intrinsic nature of the cause of the disease:

Besides DF508, more than 170 mutations in the CF

gene also cause CF.

In the United States, about 1 in 25 Caucasians

carries one CF mutation. Since tests to detect 170+

mutations are impractical, current assays use DF508

plus 6 to 12 other CF mutations (DF508+6-12) and

identify 85 to 90 percent of CF carriers (in Ashkenazic Jews, DF508+6 identifies about 95 percent of

carriers). 3 Thus, using DF508+6-12 means 10 to 15

percent of actual carriers go undetected. In other

words, a negative test result does not guarantee that

a person is not a carrier.

As mentioned earlier, a child with CF is born only

to couples where each partner is a carrier of one

CF mutation—though not necessarily the same one

for each partner. Such couples are sometimes

referred to as carrier couples, or couples who are

positive/positive (+/+). For these couples, the

chance of having a child with CF is 1 in 4 for each

pregnancy. If a couple is positive/negative (+/-)-

the father is a carrier, but the mother is not, or vice

versa—their offspring can be CF carriers, but cannot

have CF.

q Again+ using AF508 alone identifies about 70 percent of CF carriers among American Caucasians of European descent.
Chapter 1-(Surnrnary, Policy Issues, and congressional Options . 11

F

F

F

F

F

F

F A

I

I 551

x

I 551

551

x | G o

551

x | Gl D

|[ 551

x

1202

w x

1282

w x

1282

w x

1282

w x

1282

w x

.

Photo credit: Roche Molecular Systems, Inc.

DNA analysis for six common CF mutations. Unique pieces of DNA, called allele specific oligonucleotide probes, are bound to the test

strip to detect six common CF mutations; in this photograph, each individual strip runs horizontally. DNA samples from individuals of

unknown CF status are obtained, processed, and applied to separate test strips. Here, test strips for eight different individuals are shown

(rows A through H). Following hybridization and calorimetric analysis, the patterns of dots on the strips are revealed-and hence the CF

status of the individuals.

For each mutation on the strip (DF508, G542X, G551D, R553X, W1 282X, and N1303K) the left dot, if present, indicates the person

has a normal DNA sequence at that part of the CF gene. The right dot, if present, indicates the person has a CF mutation at that site.

Individual A, then, has no CF mutations at the six areas of the CF gene analyzed using this test strip, as demonstrated by single dots on

the left side for all mutations. In contrast, individuals B,D,F, and H are carriers, as demonstrated by the presence of two dots for one of the

CF mutations. Individual C has CF, as demonstrated by a single dot on the right side of the DF508 panel; individual E has CF, as

demonstrated by the single dot on the right side of the G542X panel. Individual G also has CF, but this person’s CF arises from two different

mutations—DF508 and R553X—as indicated by the pairs of dots in each of these panels.

Using DF508+6-12 means that some couples

receive test results that indicate one partner is a

carrier and one is not, when in fact the negative

partner carries one of the rare CF mutations that is

not assayed (figure 1-8). Thus, while most couples

whose test results are +/- are at zero risk of having

a child with CF, some couples with a +/- test result

actually are couples whose genetic status is +/+ (but

goes undetected) and who are at 1 in 4 risk of a child

with CF for each pregnancy. Couples with a +/- test

to have CF. Prenatal CF mutation analysis with 85

percent sensitivity could detect about 29 fetuses, but

11 would be missed. A few couples who receive a

-/-result will also be undetected carrier couples (box

l-E; table 1-2).

WHY IS CYSTIC FIBROSIS

CARRIER SCREENING

CONTROVERSIAL?

result, then, might misunderstand that their reduced Prospects of routine CF carrier screening polarize

risk of bearing a child with CF is not zero and have people. Everyone agrees that persons with a family

a false sense of security about having an unaffected history of CF should have the opportunity to avail

child. If, for example, 100,000 couples experienced themselves of CF mutation analysis, yet controversy

a first-time pregnancy, 40 fetuses would be expected swirls around using the same tests in the general
12 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 1-7—Techniques for DNA Analysis of Cystic Fibrosis Mutations

Intact DNA is chemically

extracted from the sample

Living

ceil

RESTRICTION

ENZYMES (v)

act like molecular scissors

Multiple copies of DNA sample \

larger - ELECTROPHORESIS

The DNA fragments are

separated by size into

DOT BLOT

There are over 170 mutations at the cystic fibrosis

locus (the most common mutation isA F508)

washed and floated

in a color developer

There are over 170 mutations at the cystic fibrosis

locus (the most common mutation is D F508)

SOURCE: Office of Technology Assessment, 1992.
Chapter I--Summary, Policy Issues, and Congressional Options . 13

100,000

couples

Figure 1-8-Cystic Fibrosis Mutation Test Results at 85 Percent Sensitivity

TEST RESULTS

Some of these couples

Run CF mutation test

(85 % sensitivity)

SOURCE: Office of Technology Assessment, 1992.

Box l-E-Cystic Fibrosis Carrier Tests and Detection Sensitivity

In theory, 4,000 carriers exist among 100,000 random Americans of European descent, because the carrier

frequency in this population is about 1 in 25. However, DF508+6-12 assays detect about 85 percent of people with CF

mutations, so CF carrier screening of this group would identify 3,400 of the 4,000 probable carriers. If the test were 100

percent specific, all 4,000 carriers would be identified.

Similarly, if 100,000 random couples were screened, 160 couples would be identified as +/+ (each partner a carrier)

if the test were 100 percent sensitive. One-fourth of first-time pregnancies for the 160 +/+ couples would be expected

to result in CF-affected fetuses, for a total of 40 expected CF-affected fetuses per 100,000 couples. Instead, at 85 percent

sensitivity, about 116 couples will be identified as +/+ and with each pregnancy have a 1 in 4 risk of a child with CF.

Results for 93,315 will be -/- (neither identified as a carrier), and about 6,569 couples will have +/- test results (one

partner a carrier, the other not identified as a carrier). In fact, approximately 41 of the 6,569 couples with +/- test results

are at 1 in 4 risk of bearing a child with CF in each pregnancy, while the remaining 6,528 have no risk-but these two

groups cannot be distinguished with an 85 percent test sensitivity (figure 1-8). About 4 of 93,315 couples with -/- test

results are also actually at 1 in 4 risk with each pregnancy of having a child with CF.

Thus, of the theoretical 160 +/+ couples, 116 are detectable and 44 are not when the testis 85 percent sensitive. If

all 100,000 couples experience a first-time pregnancy, 40 fetuses with CF are expected. With an 85 percent sensitive test,

29 fetuses with CF are detectable via prenatal tests, but 11 will be missed. If the assay elucidates 95 percent of carriers,

144 of 160 couples would be detected. In this case, if all 100,000 couples experience a first-time pregnancy, 36 fetuses

with CF could be detected and 4 would be missed.

With a test that detects 85 percent of individuals with CF mutations, a couple whose result is +/- has approximately

a 1 in 661 risk of having an affected child with each pregnancy (compared to a general population frequency of about

1 in 2,500). At a detection sensitivity of 95 percent, a couple with a +/- result faces a 1 in 1,964 risk of an newborn with

CF with each pregnancy. Detecting a greater proportion of carriers means couples with +/-results can be less anxious

about their risk of having a child with CF. Couples who both test negative, while not having zero risk, have a 1 in 109,200

risk of an affected child with each pregnancy at 85 percent test sensitivity.

SOURCE: Office of Technology Assessment, 1992, bawd on A.L. Beaudet Howard Hughes Medical Institute, Houston TX, personal

communications March 1992, April 1992; and W.K. Lemna, G.L. Feldman, B. Kererm et al., ‘‘Mutation Analysis for Heterozygote

Detection and the Prenatal Diagnosis of Cystic Fibrosis, ” New England Journal of Medicine 322:291-296, 1990.
14 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 1-2—Test Sensitivity and Risk of Child

With Cystic Fibrosis

Percent

mutations Couples at 1 in 4 risk Affected fetuses

detected with each pregnancy in first pregnancy

+/+ +/- -1-

Actual result result result Actual Detectable Missed

85 160 115.6 40.8 3.6 40 28.9 11.1

90 160 129.6 28.8 1.6 40 32.4 7.6

95 160 144.4 15.2 0.4 40 36.1 3.9

a per 100,000 couples.

SOURCE: A.L. Beaudet, Howard Hughes Medical Institute, Houston, TX,

personal communication, March 1992.

population. What are the elements of the controversy? Can past experiences with other carrier

screening initiatives and current research from

carrier screening pilots resolve some issues?

Today’s Clinical and Social Tensions

For years, experts theorized about confronting

CF

the

potential consequences of increased knowledge of

human genetics. In the early 1990s, the CF mutation

test moves the debate from the theoretical to the

practical. Today, along with clinical tensions surrounding CF carrier screening, are legal, ethical,

economic, and political considerations.

No mandatory genetic screening programs of

adult populations exist in the United States; OTA

finds it highly unlikely that CF carrier screening will

set a precedent in this regard. Nevertheless, people

disagree about how CF carrier screening of the

general population should be conducted.

Proponents of a measured approach to CF carrier

screening express concern about several issues that

might be raised if use of CF carrier tests becomes

routine. Invariably, discussions about CF carrier

screening raise concerns about the use of genetic

information by insurance companies and become

linked to broader social concerns about health care

reform in the United States. Related to this are

concerns about commercialization of genetic research, i.e., that market pressures will drive widespread use of tests before the potential for discrimination or stigmatization by other individuals or

institutions (e.g., employers and insurers) is assessed. Also expressed are questions about the

adequacy of quality assurance for DNA diagnostic

facilities, personnel, and the tests themselves. Opponents of widespread CF carrier screening also

wonder whether the current number of genetic

Photo credit: Lauren A. Moore

Approximately 1 in 25 American Caucasians of European descent, 1 in 46 Hispanic Americans, 1 in 60 to 65 African

Americans, and 1 in 150 Asian Americans are carriers for CF. About 25 carriers would be expected among this crowd.

Current technology would detect 85 to 95 percent of these individuals, depending on their ethnic backgrounds.
Chapter l--Summary, Policy Issues, and Congressional Options ● 15

specialists can handle a swell of CF carrier screening

cases, let alone the cases from tests for other genetic

conditions expected to arise from the Human

Genome Project. Finally, the extraordinary tensions

in the United States about abortion affect discussions about CF carrier testing and screening.

Those who advocate CF carrier tests for use

beyond affected families are no less concerned about

the issues just raised. Rather, proponents argue that

individuals should be routinely informed about the

assays so they can decide for themselves whether to

be voluntarily screened. They assert that the tests are

sensitive enough for current use and will, like most

tests, continually improve, These voices believe that

failing to inform patients now about the availability

of CF carrier assays denies people the opportunity to

make personal choices about their reproductive

futures, either prospectively--e .g., by avoiding conception, choosing to adopt, or using artificial insemination by donor or by using prenatal testing to

determine whether a fetus is affected.

Lessons From Past Carrier Screening Efforts

Carrier screening is not new to the United States.

The 1970s and early 1980s saw a number of genetic

screening efforts flourish throughout the country.

Federal legislation-chiefly the National Sickle Cell

Anemia, Cooley’s Anemia, Tay-Sachs, and Genetic

Diseases Act (Public Law 94-278; hereinafter the

National Genetic Diseases Act) and its predecessors—

fueled these programs. Today, what might work for

CF carrier screening-and what will not work-can

be gleaned from carrier screening for other genetic

disorders, even though earlier screening occurred

through more centralized efforts. In fact, some argue

that creating a defined, federally funded program for

CF carrier screening could avoid social concerns,

although others assert the contrary.

Frequently considered a successful effort, Tay -

Sachs carrier screening was initiated in 1971 at the

behest of American Jewish communities. Tay-Sachs

disease is a lethal, recessive genetic disorder that

primarily affects Jews of Eastern and Central European descent and populations descended from

French Canadian ancestors. It involves the central

nervous system, resulting in mental retardation and

death within the first years of life. Fourteen months

of technical preparation, education of medical and

religious leaders, and organizational planning preceded massive public education campaigns. Since

screening commenced, over one-half million adults

have been voluntarily screened; today, it is a part of

general medical care.

In contrast, sickle cell programs in the 1970s are

generally cited as screening gone wrong. The sickle

cell mutation—which like the Tay-Sachs and CF

mutations is recessive—affects hemoglobin, the

oxygen-camying molecule in blood. The sickle cell

mutation is found predominantly in African Americans and some Mediterranean populations. Most

individuals with sickle cell anemia live well into

adulthood. Unlike Tay-Sachs screening, much sickle

cell screening was mandatory. For the most part,

Caucasians designed and implemented programs

targeted toward African Americans, leading to

proclamations of racist genocide. Even after elimination of most mandatory screening in the late

1970s, actual practice strayed from the stated goals

of adequate genetic counseling, public education,

and confidentiality of results.

Tay-Sachs carrier screening and sickle cell

screening-along with carrier screening for other

genetic conditions (e.g., a- and ß-thalassemia)----

provide perspective for today’s discussions about

CF carrier screening. Two lessons in particular are

clear: Participation should be voluntary and public

education is vital. Disagreement exists, however,

about the degree to which CF carrier screening can

draw on the Tay-Sachs and sickle cell experiences to

resolve other considerations (e. g., discrimination).

Several factors contribute to questions raised about

comparability, including: Today’s political climate

differs; CF carrier screening has the potential to

involve larger numbers of people; and Tay-Sachs

and sickle cell screening were implemented, in part,

with explicit Government finding in a more prograromatic fashion than will be likely for CF carrier

screening.

Cystic Fibrosis Carrier Screening Pilot Studies

Opponents of routine CF carrier screening argue

that historical perspectives fall short of adequately

addressing potential adverse consequences raised by

widespread utilization of CF mutation assays, including adequate education and counseling, and

prospects for discrimination and stigmatization.

They assert that until data are gathered from

federally funded pilot projects specific to CF, carrier

screening should not be routine. Proponents, on the

other hand, argue that sufficient information is
16 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

available from privately supported CF carrier screening projects, that much historical experience applies,

and that any incremental gain that will be gleaned

from federally funded studies is insufficient to a

priori prevent routine CF carrier screening from

proceeding.

Federally Funded Studies

Despite pleas throughout the genetics community

for the Federal Government to fund pilot projects to

assess clinical and social considerations raised by

the new CF mutation analyses, initial calls for

funding of pilots went wanting. In the United

Kingdom, the CF Research Trust actively funded

and encouraged pilots (box I-F)-unlike the CF

Foundation in the United States, which has focused

on investigations to find the CF gene and mutation,

but divorces itself from CF carrier screening. Concern about abortion apparently played a major role

in the latter policy decision.

After some scrambling, the Ethical, Legal, and

Social Issues (ELSI) Program of the National Center

for Human Genome Research NCHGR), National

Institutes of Health (NH-I), stepped forward to

coordinate federally financed pilot studies. In October 1991 (fiscal year 1992), three units of NIH-the

National Center for Human Genome Research, the

National Institute of Child Health and Human

Development, and the National Center for Nursing

Research-launched a 3-year research initiative to

analyze education and counseling methods related to

CF mutation analysis.

Seven research teams, conducting eight studies,

received support and will coordinate their efforts

(box l-G). Two of seven clinical studies focus on

relatives of individuals with CF (CF carrier testing);

the other five focus on the general population. One

study involves theoretical modeling. Where appropriate, some features of the research, such as

evaluation measures and tools, cost assessment,

laboratory quality control procedures, and human

subjects protection will be standardized across sites.

Privately Funded Studies

Prior to the onset of federally sponsored pilot

projects, several public and private institutions

began to systematically offer CF carrier screening to

subsets of the population; pregnant women and their

partners, preconceptional adults, teenagers, and

fetuses all have been target populations. Most

privately funded efforts have been under way since

early 1990, and most have collected, or are collecting, data on the incidence of carrier status and

mutation frequencies. Some also follow psychosocial issues such as levels of anxiety and retention

of information. Most studies can report results, and

the various strategies used and different target

populations reflect the lack of consensus on the best

approach to CF carrier screening (table 1-3).

WHAT FACTORS WILL AFFECT

UTILIZATION?

Initially, routine CF carrier screening will likely

occur in the reproductive context; the prenatal

population has been the traditional entry point into

genetic services for many people. Preconceptional

individuals are also a possible population, but for

most individuals the first real opportunity for carrier

screening takes place post-conception. A focus on

pregnant women, however, is not without controversy. Reservations exist about abortion, as do

concerns that prenatal testing negatively shapes

perceptions of pregnancy, disability, and women.

Nevertheless, the primary responsibility for providing CF carrier screening could come to reside with

obstetricians, as has occurred with maternal serum

alpha-fetoprotein (MSAFP) screening to detect fetuses with neural tube or abdominal wall defects or

Down syndrome.

Based on the annual number of births (4.2 million)

and spontaneous abortions (an estimated 1.8 million), there are approximately 6 million pregnancies

per year for which CF carrier screening might be

performed. Twenty-four percent of women giving

birth receive no prenatal care until the third trimester, however, so CF carrier screening in the obstetric/

prenatal context could initially involve, at most, 10

million 4 men and women per year, depending on

who is screened.

For some, the key question still hovering over

carrier screening for CF is if, not when. For others,

however, the debate has shifted to when. Several

institutions already offer CF mutation analysis to

individuals, regardless of family history. OTA prod ‘rhis fi~e does notaccountfor the estimated 2.4 million infertile couples who are trying to conceive and might be interested iII CF cfier scr~tig

(would increase overall figure). Nor does it estimate the number of Americans not involved in a pregnancy (would increase), the number of individuals

involved in more than one conception per year (would decrease), or those who might have been screened during a previous pregnancy (would decrease).
Chapter l-Summary, Policy Issues, and Congressional Options ● 17
18 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box l-G-Federally Funded Cystic Fibrosis Carrier Screening Pilot Projects

In October 1991, the National Institutes of Health funded eight clinical assessments of CF carrier testing and

screening at seven institutions.

Childien’s Hospital Oakland Research Institute, Oakland, CA ($73,196). Adult siblings of CF patients and their

spouses will be interviewed to identify factors motivating or interfering with the pursuit of CF carrier testing in siblings

and their partners. In addition to examining interest in testing, this study aims to assess understanding of remits,

knowledge of medical aspects of CF, and psychological impact following testing.

Johns Hopkins University, Baltimore, MD ($314,449). The level of general interest in 1earning about CF of families

and individuals receiving care from a health maintenance organization will be examined. In particular, the study will

consider: what factors distinguish those interested in participating in a CF education program from those who are not;

examining the characteristics that differentiate people who agree to screening from participants who decide against it,

and comparing the responses of individuals identified as CF carriers to those identified as noncarriers, with emphasis

on the extent to which these responses are influenced by marital or carrier status of the partner.

UCLA School of Medicine, Los Angeles, CA ($179,067). Women of reproductive age and the partners of those who

test positive will be screened, including large numbers of Hispanic and Asian Americans, two groups that have not been

studied extensively for either their CF mutation frequencies or their response to screening and counseling. Pre- and

post-test questionnairees will be used to determine understanding of CF, predictors of consent to screening, and responses

to implications of the test results for the various ethnic and socioeconomic subgroups. Strategies for pre- and post-test

counseling will be evaluated for effectiveness.

University of North Carolina, Chapel Hill, NC ($231,916). Relatives of individuals with CF will receive pretest

education, either from a pamphlet in a private physician’s office or in a traditional genetic counseling setting.

Effectiveness of a precounseling video will be evaluated. Investigators will assess genetic and medical knowledge,

psychological status, and selected health behaviors before and after participants receive their test results.

University of Pennsylvania, Philadelphia, PA ($197,634 and $180,201). Decision theory and economic techniques

will be used to model decisionmakin“ g about CF carrier screening. The study will address: who should be offered

screening and the best method; the best course and sequence after results are delivered; rescreening negative individuals

as more mutations are identified; and the impact of future treatment on CF carrier screening. Monetary and nonmonetary

effects of the alternative strategies raised by these issues will be assessed, as well as the response to screening of

groups---i.e., patients, health care providers, and insurers-with varying financial, psychological, and moral

perspectives.

A separate clinical study will complement the theoretical work. It will analyze the decisionmaking of couples who

are offered CF carrier screening one partner at a time, and whether they choose to have the second partner screened after

a negative result for the first. When screening should be offered will be investigated.

University of Rochester, Rochester, NY ($274,110). CF mutation analysis will be offered to women of reproductive

age to determine what proportion desires it, what proportion that elects screening comprehends test results, and what

proportion of partners of screened women elects screening. Anxiety, comprehension, requests for prenatal diagnosis

despite low risk, and program costs will be assessed.

Vanderbilt University, Nashville, TN ($206,513). The feasibility of a program that incorporates pre- and post-test

education for people with negative results, and provides personal counseling to those who test positive, will be evaluated.

Written and video materials will be developed. Different settings in which CF carrier screening is offered will be

examined, as will factors that affect a couple’s decision whether or not to be screened.

SOURCE: Office of Technology Aaaeaament baaed on National Center for Human Genome Reaearch, National Inatitutes of Health, October 1991.

jects approximately 63,000 individuals will be

screened for their CF carrier status in 1992-about

a 7-fold increase over 1991 (figure 1-9). This rapid

upward trend is expected, given the nascent stage of

the technology’s movement into U.S. medical practice.

Without offering judgment on its appropriateness

or inappropriateness, OTA finds that the matter of

CF carrier screening in the United States is one of

when, not if. Regardless of the number of individuals

actually screened, it is clear that, increasingly,

patients will be informed about the availability of CF

carrier assays and a portion will opt to be screened.

What is less clear is the timeframe for physicians to

begin routinely informing patients about CF carrier

tests. It could be within a year or two, but more likely

will be a gradual process over several years. What
Chapter I--Summary, Policy Issues, and Congressional Options ● 19

Table 1-3-Privately Funded Cystic Fibrosis Carrier Screening Pilot Projects

Institution Target population Approach Findings

Baylor College of Medicine

(Houston, TX)

Cornell University Medical

College (New York, NY)

Genetics & IVF Institute

(Fairfax, VA)

McGill University

(Montreal, Canada)

Permanente Medical Group,

Inc. of Northern CaliforniaIntegrated Genetics (Framingham, MA)-VWigen(Santa

Fe, NM)

Prenatal and preconceptional

couples, with and without family

history.

Initially, couples with no family

history but enrolled in prenatal

diagnosis program for other

services; currently all couples

of reproductive age coming to

genetic services, regardless of

pregnancy status.

Women undergoing amniocentesis or chorionic villus sampling

(CVS), primarily for advanced

maternal age, offered concurrent CF mutation analysis. some

had family history.

High school students.

Pregnant women of European

Caucasian descent or Hispanic

ethnicity.

Roche Biomedical Labato- Prenatal couples.

ries(Research Triangle Park,

NC)

Two stages of mutation analysis. Both partners concurrently

screened for DF508+5. For +/-

couples, the negative partner is

analyzedfor12 additional mutations at no extra charge.

Initially DF508; since July 1991

DF508+W1282X (at least 30

percent of couples are Ashkenazic Jews). Negative partner

in +/-couples is screened for an

additional four mutations.

Initially DF508; currently with

DF508+6.

DF508

Woman is screened first for

DF50&5 mutations, with sequential screening for DF508+1 1

of partner if woman is positive.

From 1990-91, 64 at-risk pregnancies detected, of

which 14 affected fetuses were diagnosed. Fifty percent of these were electively terminated. No +/-couples

requested prenatal fetal diagnosis, no pregnancies

were terminated, and clinical evaluation did not indicate

undue anxiety.

CF carrier screening has been routinely offered

($1OO per couple) since September 1991 to all couples

of reproductive age who have contact for any reason

with Baylor’s genetic services.

As of March 1992, more than 500 couples screened

using a mouth rinse specimen at $100 per couple.

About one-third of those offered choose to participate.

Followup questionnaires indicate all appear to understand that some at-risk couples will be missed. Virtually

all agree screening should be continued, should not be

limited to those ethnic groups where detection is

highest, nor should be suspended until tests detect

more carriers. Primary reason for participation: an

interest in learning something relevant to the health of

the current pregnancy. Two reasons most often cited by

nonparticipants: carrier risk perceived as low or referring physician had not specifically recommended test.

As of August 1991, 1,327 CVS patients (44 percent)

and 370 amniocentesis patients (21 percent) opted for

fetal carrier screening. Fifty pregnancies identified as

carrier fetuses, 47 to couples with no family history.

Twelve couples declined further testing; remaining 38

sought testing for themselves.

Conducted in May 1990,40 percent of about 600 students chose to participate; two carriers were identified.

Intewiews of these individuals and their families revealed they were positive toward their new knowledge;

other family members requested testing.

Followup questionnaires revealed participants who

were negative were reasonably well-informed about the

clinical phenotype and inheritance of CF. Most understood negative test did not rule out carrier status and

were satisfied they had participated.

As of March 1992, 78 percent of women offered CF

mutation analysis have accepted (As enrollees of the

Kaiser Permanence health maintenance program, there

is no out-of-pocket expense.)

Kaiser has developed an informational and educational videotape to test on control and experimental

groups, and is using several psychosocial survey

instruments to assess individuals’ understanding of

pathology and genatics of CF, both before and after

screening. Once 5,000 individuals have participated,

Permanence Medical Group will decide whether, and

how, to proceed with CF carrier screening of plan

members.

Project is nationwide, since prior to initiation in July

1991, a letter of announcement was sent to 100

obstetricians around the country.

CF mutation analyses are performed on buccall cell

samples (mouth scrape) collected at home. The brushes

are placed in color-coded tubes for each sex, and

mailed directly to Rode by the individuals. Originally

intended to last 6 months, the timeframe has been

extended to 1 year, since subscription rate has been

Iess than expected (50 percent as of September 1991 ).
20 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 1-9—Cystic Fibrosis Carrier Screening, —

1989-92

63,000”

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9,310

6,114

1,854

I I

1989 1990 1991 1992

● Estimated

SOURCE: Office of Technology Assessment, 1992.

factors affect-or will affect-routine carrier screening for CF? Eight aspects predominate:

●

●

●

●

●

●

●

●

genetic services delivery and customs of care,

public education,

professional capacity,

financing,

stigmatization, classification, and discrimination issues,

quality assurance of clinical laboratories and

DNA test kits,

automation, and

costs and cost-effectiveness.

Of these issues, all but cost-effectiveness extend

beyond CF to global concerns about future tests to

assess other genetic risks. This section describes

OTA’s findings in each of these areas. Presented

later is an analysis of what policy issues emerge

from these findings and Congress’ role in shaping

the debate raised by these issues.

Genetic Services: Standards of Care and

Ensuring Quality

One broad question expresses a facet of the

current clinical controversy: Who serves as gatekeeper of a new technology? The degree to which

large numbers of Americans opt to learn their CF

carrier status depends first on their interaction with

the genetic services system in the country. Utilization of DNA-based CF mutation analysis will

depend on the extent to which physicians, genetic

counselors, and other health professionals customarily inform individuals about the test’s availability. In

turn, moving from innovation to standard practice

often depends on professional guidelines or statements. Disagreement exists about the applicability

of CF carrier tests to individuals without positive

family histories, which has led to tensions, with

opposite sides questioning the motives of the other.

Additionally, consumer acceptance will depend on

perceptions that the professional services they receive with screening are of high quality.

Standards of Care

Should all individuals be informed about tests to

identigy CF carrier status? Society has no definitive

way of determining when physicians should routinely advise people about the availability of tests

that could reveal their propensity to have a child with

a genetic disorder. Physician practice might be

driven by consumer demand, patient autonomy,

liability fears, economic self-interest, or a combination of these factors. CF carrier screening presents a

classic instance of the perennial problem of appropriately controlling the evolution of practice standards as a new technology becomes available. Thus,

deciding the appropriate timing for routinely telling

everyone about CF mutation tests is a contentious

issue.

Physicians can now offer individuals with no

family history of CF a test that can determine, with

85 to 95 percent sensitivity, whether they are CF

carriers. With professional opinion in a state of

flux-and knowledge of the assay’s existence continuing to spread among patients-physicians might

wonder whether they are obligated to inform patients

of its availability, even before patients ask about it.

Some consumers are interested in genetic tests

and CF carrier screening. A 1986 OTA telephone

survey of a national probability sample of adult

Americans reported that about 9 of 10 approved of
Chapter l-Summary, Policy Issues, and Congressional Options . 21

making genetic tests available through doctors.

Eighty-three percent said they would take a genetic

test before having children, if it would tell them

whether their children would probably inherit a fatal

genetic disease .

5 OTA’s 1991 survey of genetic

counselors and nurse geneticists found that 18.5

percent of respondents said they were “frequently”

or ‘‘very frequently’ asked by clients about DNAbased CF tests; about 71 percent said the number of

inquiries increased from 1989 to 1991. On the other

hand, some physicians report that actual willingness

to undertake CF carrier screening is currently

modest. In part, such reticence stems from the cost

of CF mutation analysis, which patients must

generally self-pay. It might also arise from a barrier

common to many types of medical screening: lack of

interest and reluctance to uncover what might be

perceived as potentially unpleasant news.

Generally, physicians are obligated to inform

patients of the risks and benefits of proposed

procedures, so that patients themselves may decide

whether to proceed. Where a patient specifically

asks about a test, physicians would seem obligated

to discuss the test, even if they do not recommend

that it be taken. Whether physicians are obligated to

query patients about their potential interest in a test

the provider views as unwarranted by the patient’s

circumstances depends on the customary practice of

similarly skilled and situated physicians.

Customary practice is often deterrnin ed by the

courts, and courts view statements issued by a

relevant professional society as evidence of what a

reasonably prudent physician might have done. In

mid-1992, after extended discussion, the leadership

of the American Society of Human Genetics (ASHG)

approved a revised statement that CF mutation

analysis ‘‘is not recommended’ for those without a

family history of CF. Some argue that the subtle

change in language of the new statement retreats

from the absoluteness of a 1990 ASHG statement

that stated routine CF carrier screening is ‘‘NOT yet

the standard of care. ” This view holds that the new

statement reflects an evolution of debate within the

society-that some believe CF carrier screening may

now be offered to individuals without a family

history of CF, although it might not be the ‘‘standard

of care. ’ Others argue that ASHG’s position is

unchanged—that the new statement is tantamount to

restating that CF carrier screening should not be

offered to individuals without a family history of CF.

In either case, the statement cannot be interpreted to

mean that CF carrier screening should be offered to

all individuals. The 1990 and 1991 policy statements

of professional societies and participants in an NIH

workshop stated that CF carrier screening should not

be the standard of care.

Today, some physicians take their cues strictly

from the early guidelines; the extent to which the

1992 ASHG statement will affect physician practice

remains to be seen. Others have concluded that a

general population incidence of 1 child with CF per

2,500 births, coupled with the test’s imperfect

detection sensitivity, makes routinely informing

patients about CF mutation analysis unnecessary.

Additionally, some physicians might choose not to

inform patients of the availability of CF mutation

analysis because they judge that the test is too

psychologically risky or too expensive to be worth

the possible benefits for those without a family

history of CF. Still other providers might be unaware

of the test or its possible benefits.

Some physicians, however, disagree with existing

guidelines and have already chosen to incorporate

CF screening into their practices. They believe the

assays are suffciently sensitive for general use, and

that even patients with unknown risks of conceiving

a child with CF should now have the information to

exercise choice in managing their health care. Still

other physicians might be offering the assay out of

concern that failing to could subject them to charges

of medical malpractice if a couple has a child with

CF and a court subsequently finds that CF carrier

screening had become the standard of care--despite

professional statements to the contrary. These practitioners might be concerned by the few cases where

courts held that limited adoption of a practice by

some professionals is sufficient to call into question

the reasonableness of the defendant’s Practicregardless of the extent to which that practice was

accepted generally by the profession or suggested by

professional societies. In fact, with respect to CF

carrier screening, customary physician practice might

evolve faster than that recommended by physicians’

own professional societies, as has occurred for other

practices such as amniocentesis.

5 Survey respondents were not specifically questioned about CF.
22 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Duties of Care for Genetic Counseling

Once a decision is made to offer information

about tests for CF carrier screening---or to provide

the assay itself-at least three important issues arise:

what constitutes quality genetic counseling, confidentiality of information, and compensation for

inadequate counseling or breach of confidentiality.

Components of Genetic Counseling. A genetics

professional must understand enough about the

patient’s health, his or her reproductive plans, and

available technologies so that an appropriate family

history can be obtained and necessary analyses

ordered. Less than this could give patients grounds

to complain of a false assurance of safety. More than

most aspects of medicine and counseling, genetic

counseling involves family issues and family members. For a nonspecialist, it might be enough to

recognize the need for a referral.

Having elicited information and obtained test

results, the provider must communicate the results in

a meaningful way. Translating technically accurate

information into understandable information is difficult, but essential. Effective communication also

entails recognizing and understanding religious,

psychosocial, and ethnocultural issues important to

the client and his or her family. People interpret

genetic risk information in a highly personal manner

and can misperceive, misunderstand, or distort

information. For CF carrier screening, an important

aspect involves explaining the reproductive risks the

client faces and what the condition involves. Perceptions of relative risk significantly affect qualitative

decisions. Some consumers could mistake the assay’s

resolution and perceive that a negative result from

use of the latest DNA technology means no risk.

No standard for genetic counseling exists. Some

argue in favor of a standard based on what patients

would want to know (modeled after informed

consent requirements) because there is no freed

professional norm as an alternative, and because

adequacy of the information conveyed turns more on

the values of the patient being counseled than on

professional norms. The prevailing approach in

genetic counseling, however, appears to be based on

a review of what most professionals do, rather than

what an individual patient wants.

Confidentiality. Genetics professionals with information on the carrier status of a patient are legally

obligated to keep that information confidential

.-w ”

Photo credit: Beth Fine

Genetic counseling can help individuals and families

understand the implications of positive and negative test

outcomes.

except under a few, specific circumstances. At least

21 States explicitly protect patient information

pertaining to medical conditions and treatment; it is

also part of the case law in many States without

specific statutes. Offending physicians can have

their licenses revoked or be subject to other disciplinary action. Patients whose confidential records

have been revealed can also bring civil suit against

the physician or facility.

Not all genetic information, however, must remain confidential. A provider might wish to reveal

genetic information to interested third parties without a patient’s permission. Health care professionals

are not legally liable or subject to disciplinary action

if a valid defense exists for releasing a patient’s

genetic or other medical information. With CF, the

professional might desire to inform a patient’s

relatives that they also could be at higher than

average risk of conceiving a child with CF. If the

provider is persuaded that the relatives will not be

notified-after a patient has been advised to inform

relatives that they too could carry a CF mutation—

he or she might believe that breaching confidentiality would be appropriate.

The coming years will see a growing number of

situations where health professionals will need to

balance confidentiality of patients’ genetic information against demands from relatives and other third

parties for access to that information. Overall, the
Chapter l-Summary, Policy Issues, and Congressional Options . 23

risk to the third party from nondisclosure must be

balanced against the benefit of maintaining the

expected confidentiality of the provider-patient setting. A provider contemplating disclosure to a

patient’s spouse must weigh the patient’s own

confidentiality against a spouse’s interest in sharing

decisions concerning conception, abortion, or preparation for the birth of a child with extraordinary

medical needs.

Compensation for Negligent Genetic Counseling. Inadequate genetic counseling can result in a

number of outcomes. Patients might forego conception or terminate a pregnancy when correct information would have reassured them. People might

choose to conceive children when they otherwise

would have practiced contraception, or they might

fail to investigate using donor gametes that are free

of the genetic trait they wish to avoid. Finally, they

might lose the opportunity to choose to terminate a

pregnancy.

The birth of a child with a genetic condition could

result in malpractice claims of wrongful birth or

wrongful life. For wrongful birth claims, most

jurisdictions allow compensation for negligent failure to inform or failure to provide correct information in time for parents to either prevent conception

or decide about pregnancy termination. With regard

to CF, at least one court has ruled that parents may

collect the extra medical costs associated with

managing the condition. In this case, the couple

maintained they would have avoided conceiving a

second child had their physicians accurately diagnosed CF in their first child and thus identified each

parent as a CF carrier. In wrongful life claims, the

child asserts he or she was harmed by the failure to

give the parents an opportunity to avoid conception

or birth. Most U.S. courts have been reluctant to

allow damages because they have been uncomfortable concluding that a child has been harmed by

living with severe disabilities when the only alternative is never to have been born,

Practitioners who provide inadequate genetic

counseling, including fading to recommend needed

tests, might be subject to sanctions-horn a reprimand to license revocation—by a regulatory body or

a professional society. M.D.-geneticists, as physicians, are formally licensed by States. Ph. D.-

geneticists and master ’s-level genetic counselors are

not licensed by States, but until 1992 have been

certified (along with physicians) by the American

Board of Medical Genetics (ABMG). The continued

certification of master’ s-level counselors by ABMG

beyond 1992 is uncertain.

CYSTIC FIBROSIS

IT’S YOUR

CHOICE

Photo credit: Peter T. Rowley,

University of Rochester School of Medicine

Educational materials, such as this pamphlet developed at

the University of Rochester School of Medicine, Rochester,

NY, can be useful for pretest education.
24 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Public Education

Both the way in which a provider communicates

information about potential risk to the client (or risk

to potential offspring) and the implications of the

condition and prognosis influence a client’s perception of the information. A person’s subjective frame

of reference, familiarity with genetics, and ability to

understand statistical implications of genetic risks

are also important.

Risk perception is always a more important

determinant of decisionrnaking than actual risk.

When confronting the risk of genetic disease in their

offspring, and in making reproductive decisions,

people tend to place greater weight on their ability

to cope with a child with a disability or a fatal disease

than on precise numerical risks. One study revealed

that regardless of actual risk, parents overwhelmingly see situations as O or 100 percent-it will or

will not happen—when they believe they cannot

cope with the situation.

In addition to subjective factors that influence the

interpretation of risk, most individuals have difficulty understanding risk in arithmetic terms, yet

comprehending probabilities affects people’s understanding of information provided by genetic tests.

One study of predominantly Caucasian, middleclass women in Maryland found more than 20

percent thought that “1 out of 1,000” meant 10

percent, and 6 percent of respondents thought it

meant greater than 10 percent. A 1991 national

survey of public attitudes toward genetic tests

reveals that belief in the accuracy of the technology

is one of the strongest predictors of favorable

attitudes toward genetic tests; that same survey of

1,006 Americans found that less than half were able

to answer correctly four of five technical questions

regarding genetic tests.

The need for better scientfic literacy has been a

topic of wide discussion in recent years, and

mechanisms to achieve this goal apply equally to

genetics education. Increased public education in

genetics would benefit individuals’ perceptions and

understanding about genetic test results—likely

reducing time needed for individual counseling,

Public education programs targeted to genetic

diseases have been nearly nonexistent since those

established under the National Genetic Diseases Act

were phased out in 1981. The National Science

Foundation (NSF) has supported teacher training

programs in genetics for school teachers in Kansas,

for example, but no NSF-funded, national effort

exists. Teachers who participated in the Kansas

program subsequently increased time devoted to

genetics instruction at the high-school level by

three-fold. Instruction in elementary schools increased 22-fold. More recently, the U.S. Department

of Energy (DOE) began funding a 3-year project to

prepare 50 selected science teachers per year to

become State resource teachers.

Public education can go a long way toward

preparing individuals for the decision of whether and

when to be screened. Positive and negative experiences with large-scale Tay-Sachs, sickle cell, and

a-and ß-thalassemia carrier screening programs—

in the United States and abroad-demonstrate the

value and importance of pretest community education.

Professional Training and Education

Many types of health professionals perform genetic counseling: physicians, Ph.D. clinical geneticists, genetic counselors, nurses, and social workers. Critics of widespread CF carrier screening

question whether the present genetics counseling

system in the United States can handle the swell of

cases if CF carrier screening becomes routine.

Currently, about 1,000 master’ s-level genetic

counselors practice in the United States. An additional 100 nurse geneticists provide similar services.

The ABMG has certified 630 professionals in

genetic counseling, including master’ s-level genetic

counselors, nurses, and M.D. and Ph.D. geneticists.

If genetic counseling for CF carrier screening were

to fall only to board-certfiled professionals, the

available number of professionals might be short of

what is needed. OTA’s survey of genetic counselors

and nurses in genetics also indicates that respondents believe routine CF carrier screening will strain

the present genetic services delivery system. Respondents estimated that, on average, 1 hour would

be needed to obtain a three-generational family

history and to discuss CF carrier screening and

genetic risks.

6&@ OTA uses the term * ‘genetlC co~seb’ to specifically describe master’ s-level individuals certified by the ABMG (or board-eligible)

because legal distinctions in licensing and reimbursement for services exist among the different types of professionals who perform genetic counseling.
Chapter l--Summary, Policy Issues, and Congressional Options ● 25

Skeptics of a persomel shortage assert that

counseling about CF carrier assays is likely to take

place in the general obstetric/prenatal context, however, and they believe 1 hour exaggerates the amount

of time that suffices for all prenatal tests, let alone

only CF carrier screening. Furthermore, counseling

related to CF carrier screening is likely to extend

beyond board-certified individuals to include other

physicians and allied health professionals. For

example, an unknown number of social workers,

psychologists, and other public health professionals

perform genetic counseling, often to minority and

underserved populations.

ultimately, the issue of adequate services and

professional capacity could turn on the extent to

which patients receive genetic services through

specialized clinical settings, as they largely do now,

versus access through primary care, community

health, and public health settings. Overall, OTA

cannot conclude whether increased numbers of

genetic specialists are necessary-arguments exist

pro and con. One finding is clear: Increased genetics

education for all health care professionals is desirable. Routine carrier screening for CF—and tests yet

to be developed for other genetic conditions—will

require adequate training and education of individuals in the broader health care delivery system.

Increasing professional education in genetics will

not be an easy task. The average 4-year medical

school curriculum includes 21.6 hours of genetics

instruction. Fifteen master’ s-level programs in genetic counseling exist, producing approximately 75

graduates per year. Of 200 U.S. universities that

offer graduate nursing degrees, only 4 offer programs providing a master’ s-level genetics major.

Only 9 of nearly 100 accredited social work graduate

programs in the United States offer special courses

on genetic topics. Few schools of public health offer

genetics as part of their curriculum; none requires it.

Federal support for genetic services, education,

and training has changed dramatically since 1981.

Prior to 1981, genetics programs applied through

their State for Federal funds under the National

Genetic Diseases Act (Public Law 94-278). With

creation of the Maternal and Child Health (MCH)

Block Grant (Public Law 97-35), State genetic

services now compete with other maternal and child

health initiatives (box l-H). Additionally, Federal

spending on demonstration projects for service

delivery, training, and education has declined after

adjustment for inflation. Training support for master ’slevel genetic counselors is minimal. The U.S.

Department of Health and Human Services (DHHS)

provides no fmancia1 support for trainin g genetic

counselors or for improving genetics education in

medical schools. Through support to the Council of

Regional Networks for Genetic Services (CORN),

DHHS provides funds for some continuing professional genetics education programs for physicians,

but not for other genetics professionals.

Financing

Health insurance in the United States is not

monolithic. U.S. health care financing, which totaled more than $800 billion in 1991, is a mixture of

public and private funds. Federal financing includes

Medicare, Medicaid, and the Civilian Health and

Medical Program of the Uniformed Services (CHAMPUS). Private funding mechanisms include selffunded plans, commercial health insurance plans,

Blue Cross and Blue Shield (BC/BS) plans, health

maintenance organizations (HMOs), self-pay, and

nonreimbursed institutional funding. State high-risk

pools—generally using public and private moniesare also an option in some States for people who

cannot obtain private health insurance. Rules and

regulations governing each sector vary.7 Thus,

separating how the current financing paradigm

might affect CF carrier screening-and vice versa—

is difficult.

For the majority of Americans, access to health

care, and the health insurance that makes such access

possible, is provided through the private sector.

Some acquire health insurance on their own through

individual policies; 10 to 15 percent of people with

health insurance have this type of coverage. Of

group policies, about 15 percent have some medical

underwriting —i.e., medical and genetic information

are used to determine eligibility and premiums for

health insurance. A large majority of insured individuals and their family members—1 63 million of

the 214 million with health care coverage-obtain

coverage via employer-offered large group policies

with no medical underwriting. The employer, in

7 Benefit packages offered by the different providers vary, as do laws goverrung them. Except for self-funded company health insurance plans, State

laws govern both group and individwd private heaIth insurance. Thus, a patchwork of laws and regulations oversees commercial insurers. Laws and

regulations for commercial imurers differ from those for BC/BS plans. HMOS are regulated by States, with some Federal guidance.
26 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box l-H-Genetic Services: Federal-State Partnership

Funding for genetic services derives from a medley of Federal and State sources, and varies greatly from State

to State. During the 1970s, genetic services enjoyed substantial Federal funding, in part through congressional mandate.

The Omnibus Budget Reconciliation Act of 1981 (Public Law 97-35), however, led to the consolidation of genetic

services funding-along with seven other programs-into the Maternal and Child Health (MCH) Block Grant. Overall,

funding for maternal and child health services was cut, and the responsibility for distributing the monies and for

providing services was passed to the States, which also had to begin using $3 of State funds for every $4 of Federal

money received. Prior to the block grant, no matching funds were required.

Under provisions of the MCH block grant, 85 percent of funds go directly to the States for maternal and child

health services. States must decide how to allocate the funds among a number of areas, such as general prenatal care,

infant nutritional supplementation, and other maternal and child health needs. MCH funds may be used for health care

services, education, and adminis“ tration. In fiscal year 1990, less than 2 percent of MCH funds were used by States to

support genetic services other than newborn screening.

In general, MCH funds account for a small portion of State genetic services. Under terms defined by the block

grant, each State decides whether or how much money to designate for genetic services. In 1990,34 States used MCH

funds to support some aspect of general genetic services other than newborn screening, including nonpatient-related

activities such as administration and planning. In the majority of States, however, MCH funds accounted for less than

25 percent of fiscal year 1990 finding for genetic services. In fiscal- year 1990, MCH finding for genetic services other

than newborn screening totalled approximately $8 million; State funding accounted for approximately $22 million.

Fifteen percent of the MCH block grant is administered as direct grants for Special Projects of Regional and

National Significance (SPRANS). SPRANS monies are grants for specific projects and are not given to each State.

SPWS provides seed money for demonstration, or pilot, projects in a number of areas. After the demonstration

period ends, usually in 3 years, alternative funding must be found.

In fiscal year 1990, genetic services received about 9 percent of all SPRANS funds. When adjusted for inflation,

however, constant dollar funding for genetic services under SPRANS has decreased almost every year since the block

grant’s inception. Moreover, SPRANS support of genetic services has decreased from about 90 percent of the SPRANS

genetic services budget in 1981 to approximately 66 percent in 1991. Initially, most of the SPRANS genetic services

budget established statewide genetics programs, with each State receiving seed money for at least 4 years. The last State

received funding in 1990. Other areas of genetic services delivery receiving SPRANS support include ethnocultural

projects to increase utilization of genetic services by underserved populations; psychosocial studies; and support

groups for young adults and families. In fiscal year 1990, 16 States used approximately $4 million from SPRANS

grants to support demonstration projects in clinical genetic services other than newborn screening. In fiscal year 1990,

just over one-third of SPRANS’ genetic services budget went to the regional networks and the Council of Regional

Networks for Genetic Services (CORN). CORN and the regional networks-comprised of genetic service providers,

public health personnel, and consumers-serve as resources for communication and coordinate data collection and

quality assurance, but do not provide direct services to patients.

In addition to block grant and SPRANS awards, States also fund genetic services from other sources. In fiscal year

1990, at least 26 States derived $46 million in genetic services funding exclusive of newborn screening from provider

in-kind and service charges, third-party reimbursement, grants, contracts, newborn screening fees, health insurance

surcharges, and mental health/mental retardation funds. For some States, such funding accounts for most of their

genetic services funding. For example, newborn screening fees generated 93 percent of genetic services funding in

Colorado and 86 percent in Michigan in fiscal year 1990. Similarly, prenatal screening service fees accounted for more

than 83 percent of the genetic services budget in California in fiscal year 1990.

All States, the District of Columbia, and Puerto Rico coordinate genetic services statewide; nearly half

experienced a decrease in funding for genetic services from fiscal years 1988 through 1991. Individual State genetic

service programs face yearly uncertainty about how much-if any—funding they will receive, which makes planning

difficult. As general knowledge and public awareness about genetic diseases continues to emerge out of the Human

Genome Project, uncertainty in genetic services funding will be increasingly problematic.

SOURCE: Office of Technology Assessrnent, 1992 based on E. Duffy, Genetic Services Branch, Maternal and Child Health Bureau U.S.

Department of Health and Human Services, Rockville, MD, penonal communication February 1992; and F.J. Meaney, “CORN

Report on Funding of State Genetic Services Programs in the United States, 1990,” contract document prepared for the U.S. Congress,

Office of Technology Assessment April 1992.
Chapter I-Summary, Policy Issues, and Congressional Options ● 27

turn, contracts with a commercial insurer, a BC/BS

plan, an HMO, or is self-funded.

Self-funded health insurance plans are group

policies that merit specific discussion, since they are

creatures of Federal, not State, law. Since enactment

of the Employee Retirement Income Security Act of

1974 (ERISA; 29 U.S.C. 1131 et seq.), many

companies find self-finding beneficial because their

employee benefit plans are not subject to State

insurance regulation. With an ERISA plan, the

employer directly assumes most or all of the

financial liability for the health care expenses of its

employees, rather than paying premiums to other

third-party payers to assume that risk. Self-funded

companies enjoy considerable latitude in designing

employee coverage standards. Today, about 53

percent of the employment-based group market is

self-funded, and therefore unregulated by the States.

In large measure, the number of people who opt

to be screened could hinge on who pays, or will pay,

for the cost of CF mutation analyses-the individual

or a third-party payor. As mentioned previously,

some physicians report that reluctance to undertake

CF carrier screening seems to stem from the test’s

cost. Physicians seeing patients who rely on health

insurance to cover part of their expenses usually

inform them that their coverage probably precludes

reimbursement for CF mutation analysis without a

family history of CF,8 and so if they opt to be

screened, they will likely need to self-pay. For

laboratories that perform genetic tests, the issue of

reimbursement also might be crucial to the ultimate

volume of future business in this area.

Private Sector Reimbursement

Health insurance industry representatives assert

that most companies will not pay for tests they

consider screening assays. Thus, reimbursement for

CF carrier tests in the absence of family history will

likely remain on a self-pay basis unless they become

part of routine pregnancy care-again, as happened

for MSAFP screening.

OTA’s 1991 survey of commercial insurers,

BC/BS plans, and HMOS

9 confirms these policies

for individual contracts or medically underwritten

groups. OTA found carrier tests for CF, Tay-Sachs,

and sickle cell would not be covered by 12 of 29

commercial insurers offering individual coverage

for any reason-screening or family history. NO

company offering individual insurance or medically

underwritten policies would cover CF carrier analysis if a patient requested it, but had no family history.

If there is a family history, most companies would

pay for carrier tests. Similar results were found for

BC/BS plans and HMOs, although a few BC/BS

plans and a few HMOs reported they would cover

carrier tests performed for screening purposes.

As mentioned earlier, initial carrier screening for

CF will likely take place in the context of obstetric/

prenatal care. For all three respondent populations,

prenatal screening tests for CF generally are not

covered without a family history, although more

would cover prenatal tests solely at patient request

(without family history) than cover general carrier

screening. Some respondents covered no prenatal

tests.

Respondents were asked to indicate whether they

agreed or disagreed with the following scenario:

Through prior genetic testing, the husband is

known to be a carrier for CF. Before having children,

the wife seeks genetic testing for CF. The insurance

company declines to pay for the testing, since there

is no history of CF in her family.

For commercial insurers who write either individual policies or medically underwrite group policies,

or both, 21 medical directors (41 percent) agreed

strongly or somewhat with this scenario; 28 respondents (47 percent) disagreed somewhat or disagreed

strongly. In part, these results reflect OTA’s survey

8 Under the present health care system and current reimbursement policies by insurers, the reality is that the opportunity to be screened depends on

the ability to self-pay (except for Medicaid). Thus, questions of access to CF carrier tests and genetic semicm arise. However, the issue of access to @

carrier screening is no different-and inextricably linked-to the broad issue of health care access in the United States, a topic beyond the scope of this

report.

Some contend that until the issue of access is resolved, widespread carrier screening should not proceed. On the other hand, others argue that inequitable

access is true for health care in the United States, generally. Supporters of carrier screening for C!F question why access to genetic tests and services should

be held to a higher standard. In this report, OTA anatyzes the issue in the context of today’s health care systeu but points out that for some opponents

of routine CF carrier screening, nonuniversal access is an a priori reason for why CF carrier screening should not proceed.

g OTA~s suney of he~th &Wers does not measue ac~~ practice, ~ess othewise specifically indicated. The information presented here shodd

not be interpreted to represent numbers or percentages of entities who actually have dealt with these issues. Health insurers who write individual policies

or medically underwritten groups were asked to speculate how they would treat certain conditions or scenarios presented (currently or in the future,

depending on the question), not whether they, in fact, had made such decisions.
28 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

finding that several respondents would not cover any

carrier tests, even when medically indicated by a

family history. On the other hand, not all respondents who agreed with the scenario represented these

companies. These individuals appeared not to understand that the situation was not a case of CF carrier

screening, but one of testing to ascertain the couple’s

risk of conceiving an affected fetus in light of the

male’s family history.

OTA also found variation in how genetic counseling is covered by commercial insurers, BC/BS plans,

and HMOs that offer individual policies or medically underwritten group coverage. OTA’s survey of

genetic counselors and nurse geneticists confirms

these results: Reimbursement for genetic counseling

by these professionals is more likely when a family

history exists.

Finally, as stated earlier, most people obtain

health care coverage through group policies. Determining how these thousands of policies would

reimburse for CF carrier screening was not possible

for this report. Nevertheless, information gathered

informally indicates group policy coverage is unlikely to differ significantly from OTA’s survey

results-i. e., most policies will not cover CF carrier

assays unless there is a family history. The Federal

Office of Personnel Management, which oversees

Federal employee health benefits, has denied reimbursement for preconception CF carrier screening

because it views it as preventive, not therapeutic. On

the other hand, one private institute’s experience

with reimbursement to clients for elective fetal CF

carrier screening paints a different picture. In a small

survey of clients, 16 of 27 reported they had been

reimbursed for their tests. Eleven had been reimbursed fully-by either commercial insurers or

BC/BS plans-and five had been partially reimbursed. It is likely that reimbursement occurs more

frequently in this population than might be expected

from OTA’s survey because it occurs in the context

of pregnancy management, not preconception.

Public Sector Reimbursement

Although access to CF carrier tests will largely

depend on ability to pay because most private

insurance does not cover them-at least to the extent

that individual policies reflect group polices-some

individuals will be Medicaid eligible. Reimbursement for their assays would be partially covered by

this State-Federal partnership. In 1991, OTA surveyed directors of State Medicaid programs and

Table 1-4-Medicaid Reimbursement for

Genetic Proceduresa

Not Individual

Covered Covered consideration Unknown

Amniocentesis. . . . . . . 45 0 1 0

Chorionic villus

sampling. . . . . . . . . 31 10 4 1

Ultrasound. . . . . . . . . . 44 0 2 0

Maternal serum alphafetoprotein test. . . . . 44 0 2 0

DNAanalysis. . . . . . . . 26 6 6 8

Chromosome

analysis. . . . . . . . . . 41 1 4 0

Genetic counseling. . . 1 1

b

19 2 3

aBased on the responses of 45 states and the District of Columbia to a 1991

OTA survey of Medicaid programs.

bElevenother States cover genetic counseling only as apart of office visits.

SOURCE: Office of Technology Assessment, 1992.

found State to State variation in both the types of

genetics and pregnancy-related services covered

(table 1-4) and the amounts reimbursed to providers

for those services. Some States do not cover certain

services at all. For all States and services, the dollars

reimbursed fall short of the procedures’ actual

charges.

Stigmatization, Classification, and

Discrimination

Concern is expressed that CF carrier screening

might be sought or offered despite an uncertain

potential for discrimination or stigmatization by

other individuals or institutions (e.g., employers and

insurers). Stigmatization of, or discrimination against,

persons with certain diseases is not unique to

illnesses with genetic origins. Yet as the number and

scope of predictive genetic tests increase, so does

concern about how perceptions of and behavior

towards carriers (or individuals identified with

predispositions) will develop.

Stigmatization and Carrier Status

While a relationship exists between a characteristic’s visibility and the amount of stigma it induces,

invisible characteristics (e.g., carrier status) are also

stigmatized. Stigmatization of CF carriers will

probably focus on the notion that it is irresponsible

for people who are at genetic risk to knowingly

transmit a condition to their children (box l-I). A

1990 national survey of Americans reported 39

percent said “every woman who is pregnant should

be tested to determine if the baby has any serious

genetic defects. ” Twenty-two percent responded
Chapter I-Summary, Policy Issues, and Congressional Options ● 29

Box 1-I—Bree Walker Lampley and Preventing Versus Allowing Genetic Disability

In July 1991, Los Angeles radio talk show host Jane Norris launched a firestorm of controversy when she

solicited listener comments on Los Angeles television anchorwoman Walker Lampley’s pregnancy. Making

her disapproval clear, Norris said:

We’re going to talk about a woman in the news and I mean that literally. She’s a very beautiful, very pregnant

news anchor, and Bree Walker also has a very disfiguring disease. It’s called syndactyly [sic] and the disease is very

possibly going to be passed along to the child that she’s about to have. And our discussion this evening will be, is

that a fair thing to do? Is it fair to pass along a genetically disfiguring disease to your child?

Bree Walker Larnpley has ectrodactyly, a genetic condition manifest as the absence of one or more fingers or

toes. It is an autosomal dominant disorder hence her potential offspring have a 50-50 chance of inheriting

ectrodactyly. Noris’ show highlighted the public tension that exists over attitudes toward preventing genetic

disability, illness, and disease.

Some listeners agreed with Norris’ opinion against knowingly conceiving a child who would be at 1 in 2 risk

of “this deformity-webbed hands. . . .“ One caller stated she would “rather not be alive than have a disease like

that when it’s a 50-50 chance. ” Other callers compared her comments to racism and eugenic genocide: “. . this

tone of yours that just kind of smacks of eugenics and selective breeding. . . . Are you going to talk in the next hour

about whether poor women should have kids?”

The opinions offered illustrate the concern over the potential for discrimination or stigmatization as personal

knowledge of one’s genetic makeup increases. Shortly after the program aired, one disability rights activist pointed

out that the radio show reminded her of her discomfort with the Human Genome Project.

On August 28, 1991, Bree Walker Lampley delivered a healthy baby boy, who has ectrodactyly. In October

1991, arguing that a biased presentation with erroneous information was broadcast, Walker Lampley was joined by

her husband, several groups, and other individuals in filing a complaint with the Federal Communications

Commission (FCC). Norris and the radio station stand by their right to raise the issue and “have no regrets.’ The

FCC rejected Walker Lampley’s complaint in February 1992, and no appeal is planned.

SOURCE: Offlce of Technology Assessment, 1992, based unassociated Press, “FCC Rejeets Anehorwoman’s Complaint Over Call-In Radio

Show,” Feb. 14, 1992; J. Mathews, The Debate Over Her Baby: Bree Walker Lampley Has a Deformity. Some People Thi.nk She

Shouldn’t Have Kids,’ Washington Post, Oct. 20, 1991; and J. Seligrnann “Whose Baby Is It, Anyway?, ’’Newsweek, Oct. 28,1991.

that regardless of what they would want for them- How CF—as a condition—is viewed by Ameriselves, ‘‘a woman should have an abortion if the

baby has a serious genetic defect. ” Nearly 10

percent believed laws should require a woman to

have an abortion rather than have the government

help pay for the child’s care if the parents are poor.

Few empirical studies have exarnined stigmatization of CF carriers directly, but relevant research

funded through the NIH/DOE ELSI Programs of the

Human Genome Project is under way. One study in

Montreal, Canada, reports carriers generally expressed positive views about their newly determined

carrier status (screening for DF508 only). Most (68

percent) would want their partner tested, and 60

percent said if the partner were a carrier, it would not

affect the relationship. Existing research on genetic

carriers and stigmatization, generally for Tay-Sachs

or sickle cell, have some bearing on carrier screening

for CF---chiefly that public education is crucial to

overcoming stigmatization.

cans will affect perceptions and potential reproductive stigma of CF carriers. Of prime importance is a

commitment to nondirective genetic counseling to

reduce perceived biases so individuals can make

informed choices about bearing children with CF.

Such a professional commitment coupled with

increased public awareness and education about CF

carrier screening could reduce potential problems of

stigmatization of CF carriers, as well as stigmatization for other disorders as genetic screening evolves

through the 1990s and beyond.

Health Care Coverage Access

One of the most frequently expressed concerns

about CF carrier screening specifically, and genetic

tests generally, is the effect they will have on health

care access and risk classfication in the United

States. Consumers fear being excluded from health

care coverage due to genetic and other factors. Such
30 ● Cystic Fibrosis arid DNA Tests: Implications of Carrier Screening

Photo credit: American Philosophical Society

Eugenics Building, Kansas Free Fair, 1929.

fears persist despite the fact that most contracts for

individual health insurance coverage preclude blanket nonrenewal. Similarly, an insurer cannot raise

rates for an individual who has been continuously

covered if the person develops a new condition. Of

special import to small group policies is that it is

legal for an insurer not to renew a group contract, or

to renew with a steep premium increase, based on the

results of one individual’s genetic, or other medical,

test. Group policies are rarely guaranteed renewable,

and most people in the United States are covered by

group policies. Many group policies have preexisting condition clauses that preclude, for some

period of time, reimbursement for expenses related

to health conditions present on the policy’s effective

date.

One nationwide survey revealed 3 in 10 Americans say they or someone in their household have

stayed in a job they wanted to leave mainly to

preserve health care coverage. A 1989 OTA survey

of Fortune 500 companies and a random sample of

businesses with at least 1,000 employees found 11

percent of respondents assessed the health insurance

risk of job applicants on a routine basis; another 25

percent assessed health risks sometimes. Nine percent of these respondents also took into account

dependents’ potential expenses when considering an

individual’s application. Forty-two percent of respondents said the health insurance risk of a job

applicant reduced the likelihood of an otherwise

healthy, able job applicant being hired.
Chapter I-Summary, Policy Issues, and Congressional Options ● 31

Figure I-l O-Genetic Conditions as Preexisting

Conditions: Health Insurers’ Attitudesa

87

5

—

3

Commercials HMOs BC/BS plans

_ Agree strongly or somewhat

~ Disagree strongly or somewhat

~ No response

Genetic conditions, such as cystic fibrosis or Huntington

disease, are preexisting conditions.

offer individual policies or medically underwritten group policies.

SOURCE: Office of Technology Assessment, 1992.

Figure l-n-Carrier Status as a Preexisting

‘Condition: Health Insurers’ Attitudesa -

56

4

l - -

55

Commercials HMOs BC/BS plans

_ Agree strongly or somewhat

-- Disagree strongly or somewhat

-- No response

Carrier status for genetic conditions, such as cystic fibrosis or

Tay-Sachs, are preexisting conditions.

aBaSed on responses to a 1991 OTA survey of commercial insurers, health

maintenance organizations, and Blue Cross and Blue Shield plans that

offer individual policies or medically underwritten group policies.

SOURCE: Office of Technology Assessment, 1992.

Figure 1-1 2-Genetic Information as Medical

Information: Health Insurers’ Attitudesa

69

53

9

Commercials HMOs BC/BS plans

_ Agree strongly or somewhat

-- Disagree strongly or somewhat

-- No response

Genetic information is no different than other types of

medical information.

a Based on responses to a 1991 OTA survey of commercial insurers, health

maintenance organizations, and Blue Cross and Blue Shield plans that

offer individual policies or medically underwritten group policies.

SOURCE: Office of Technology Assessment, 1992.

OTA found the majority of respondents to its

health insurers’ survey ‘‘agree strongly’ or “agree

somewhat’ that illnesses with genetic bases, such as

CF or Huntington disease, are preexisting conditions

(figure 1-10). Thus, insurers would exclude reimbursement for such conditions for a period of time if

the person could obtain individual or medically

underwritten insurance at all. More surprising, since

carriers have no symptoms of the disorder, is the

finding that respondents, collectively, are nearly

evenly split on whether carrier status+. g., for CF

or Tay-Sachs—is a preexisting condition (figure

1-11).

OTA’s survey also revealed that genetic information is, for the most part, viewed no differently than

other types of medical information (figure 1-12).

Personal and family medical histories were the most

important factors in determiningg insurability, according to survey respondents. OTA found medical

directors and underwriters felt less strongly about

“genetic predisposition to significant conditions”

as a facet of insurability than they did about medical

history. Of significance to CF carrier screening, a

minority of all types of insurers found carrier risk

‘‘very important’ or ‘‘important’ to insurability.
32 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Twenty-four percent (7 respondents) of medical

directors at commercial insurers writing individual

policies said “carrier risk for genetic disease” was

“very important” or “important’ to insurability; 18

percent (2 respondents) of HMOs responded similarly, as did 8 percent (2 respondents) of BC/BS

chief underwriters.

Although an insurer might consider carrier status

important to evaluating an application, carrier status

does not appear to translate into difficulties for

applicants in ultimately obtaining health care coverage from OTA’s survey respondents. Ninety-three

percent of respondents from commercial insurers

and all HMOs offering individual coverage would

accept the person with standard rates if the applicant

was asymptomatic but had a family history of CF.

For BC/BS plans, however, 55 percent would accept

at standard rates, 21 percent would accept at the

standard rate with an exclusion waiver, and 7 percent

would decline to cover the CF carrier. For those who

responded they would accept with an exclusion

waiver or decline to cover, reluctance to offer

standard insurance might stem from not wanting to

pay for possible children or from a misunderstanding

of the meaning of CF carrier status.

Overall, OTA’s survey reveals genetic information is not viewed as a special type of information.

In making decisions on insurability and rating based

on genetics, what seems important is the particular

condition (e.g., CF disease, diabetes, sickle cell

anemia), not that the condition is genetically based.

The increased availability of genetic information,

however, adds to the amount of medical information

that insurers can use for underwriting. The availability of this additional information leads to concern

that risk assessments will become so accurate on an

individual level as to undermine the risk-spreading

function of insurance. This, of course, would have

profound societal implications.

Perspectives on the Future Use of Genetic Tests

by Health Insurers

Commercial insurers, HMOs, and BC/BS plans

already use genetic information in making decisions

about individual policies or medically underwritten

groups. People seeking either of these types of

coverage reveal such information as part of the

battery of questions to which applicants respond in

personal and family history inquiries. OTA is

unaware of any insurer who underwrites individual

or medically underwritten groups and requires

carrier or presymptomatic tests-e. g., for Huntington or adult polycystic kidney diseases. Even a

decade from now, OTA’s survey data indicate the

vast majority of respondents do not expect to require

genetic tests of applicants who have a family history

of serious genetic conditions, nor do they anticipate

requiring carrier assays even if a family history

exists (table 1-5).

Health insurers do not need genetic tests to find

out genetic information. It is less expensive to ask a

question or request medical records. Thus, whether

genetic information is available to health insurers

hinges on whether individuals who seek personal

policies or are part of medically underwritten groups

become aware of their genetic status because of

general family history, because they have sought a

genetic test because of family history, or because

they have been screened in some other context.

OTA’s survey reveals health insurers are concerned about the potential for negative financial

consequences if genetic information is available to

Table 1-5-Projected Use of Genetic Information by Insurers in 5 and 10 Years
Chapter 1---Summary, Policy Issues, and Congressional Options ● 33

the consumer, but not them. Thirty-four medical

directors (67 percent) from commercial insurers said

they “agree strongly” or “agree somewhat” with

the statement that ‘ ‘it’s fair for insurers to use

genetic tests to identify individuals with increased

risk of disease. ’ Thirty-eight respondents (74 percent) from commercial insurers agreed strongly or

somewhat that an insurer should have the option of

determining how to use genetic information in

determining risks. ’ ‘

Access to Health Insurance After Genetic Tests

Existing information about how genetic test

results currently affect individuals’ health care

coverage is largely anecdotal. One case from the

Baylor College of Medicine (Houston, TX) illustrates why concern is expressed about health insurance and genetic screening and testing:

A couple in their 30s has a 6-year-old son with CF.

Prenatal diagnostic studies of the current pregnancy

indicate the fetus is affected. The couple decides to

continue the pregnancy. The HMO indicated it

should have no financial responsibility for the

prenatal testing and that the family could be dropped

from coverage if the mother did not terminate the

pregnancy. The HMO felt this to be appropriate since

the parents had requested and utilized prenatal

diagnosis ostensibly to avoid a second affected child.

After a social worker for the family spoke with the

local director of the HMO, the company rapidly

reversed its position.

Consumers and patient advocates maintain such

situations represent the tip of an iceberg. They assert

individuals who avail themselves of genetic tests

subsequently have difficulty obtaining or retaining

health insurance. Health insurance industry officials

argue to the contrary. If the problem was prevalent,

they assert, ample court cases could be cited because

patients and their attorneys would not be passive

recipients of decisions such as that just described.

To explore this issue, OTA asked third parties—

nurses in genetics and genetic counselors-for their

experiences. In 1991, at least 50 genetic counselors

or nurses in clinical practice (14 percent of survey

respondents) reported knowledge of 68 instances of

patients who experienced difficulty with health

insurance due to genetic tests (table 1-6).10

It is important to note that most cases described in

table 1-6 do not involve recessive disorders and

carrier screening for conditions like CF, but involve

situations in which genetic test results appear to have

been treated the same as adverse test results for

nongenetic conditions. Access to health care coverage for CF carriers presumably should not be an

issue because CF carriers have no symptoms of the

disorder, although OTA’s survey of health insurers

indicates otherwise in a small fraction of cases. For

genetic testing or screening to detect genetic illness

(or the potential for illness), however, the possibilities for problems are already unfolding.

The OTA data permit neither extrapolation about

the actual number of cases that have occurred in the

United States, nor speculation about trends. An

estimated 110,600 individuals were seen in 1990 by

the genetic counselors and nurses responding to

OTA’s survey, but OTA did not advise respondents

to limit descriptions of clients’ insurance difficulties

to 1990; it is unlikely that all reported cases occurred

in 1990.

The Americans With Disabilities Act of 1990 and

Genetics

In 1990, Congress enacted the Americans With

Disabilities Act (ADA; Public Law 101-336), a

comprehensive civil rights bill to prohibit discrimination against individuals with disabilities. The

ADA encompasses private sector employment, public services, public accommodations, and telecommunications. It does not preempt State or local

disability statutes.

Under the ADA, a person with a disability

includes someone who has a ‘‘record’ of or is

‘‘regarded’ as having a disability, even if no actual

incapacity currently exists. A “record’ of disability

means the person has a history of impairment. This

provision protects those who have recovered from a

disability that previously impaired their life activities (e.g., people recovered from diseases such as

cancer who might still face discrimination based on

misunderstanding, prejudice, or irrational fear).

Additionally, individuals regarded as having disabilities include those who, with or without an

impairment, do not have limitations in their major

life functions, yet are treated as if they did have such

10 OTA dW~ not judge tie “~di~_positively or negatively+f he claims. some cases might have been settled k favor of the individual @USe

the initial judgment was deemed improper or illegal. Others might have been cases where an applicant attempted to select against an insurer by

misrepresenting his or her health history, which would have been resolved against the individual.
34 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 1-6-Case Descriptions of Genetic Testing and Health Insurance Problemsa

Positive test for adult polycystic kidney disease resulted in canceled policy or increased rate for company of newly diagnosed individual.

Positive test for Huntington disease resulted in canceled policy or being denied coverage through a health maintena organization.

Positive test for neurofibromatosis resulted in canceled policy.

Positive test for Marfan syndrome resulted in canceled policy.

Positive test for Down syndrome resulted in canceled policy or increased rate.

Positive test for alpha-1 -antitrypsin defined as preexisting condition; therapy related to rendition not covered.

Positive test for Fabry disease resulted in canceled policy.

Woman with balanced translocation excluded from future maternity coverage.

Positive Fragile X carrier status and subsequent job change resulted in no coverage.

After prenatal diagnosis of hemophilia-affected fetus, coverage denied due to preexisting condition clause.

Denied coverage or encountered diffculty retaining coverage after birth of infant with phenylketonuria.

Woman diagnosed with Turner's syndrome denied coverage for cardiac status based on karyotype. Normal electrocardiogram failed to

satisfy company.

Family with previous Meckel-Gruber fetus denied coverage in subsequent applications despite using prenatal diagnosis and therapeutic

abortion.

Mother tested positive as carrier for severe hemophilia. Prenatal diagnosis revealed affected boy; not covered as preexisting condition

when pregnancy carried to term.

After a test revealed that a woman was a balanced translocation carrier, she was initially denied coverage under spouse’s insurance

because of risk of unbalanced conception. Subsequently overturned.

Woman without prior knowledge that she was an obligate carrier for X-linked adrenoleukody strophy found out she was a carrier. She

had two sons, both of whom were healthy, but each at 50 percent risk. Testing was done so they could be put on an experimental

diet to prevent problems that can arise from mid- to late childhood or early adulthood. One boy tested positive. The family’s private

pay policy (Blue Cross/Blue Shield) is attempting to disqualify the family for failing to report the family history under preexisting

conditions.

After birth of child with CF, unable to insure unaffected siblings or themselves.

alggl OTA suwey of genetic ~unselors and nurses in genetics. Not all cases, or multiple cases involving same disorder, listed.

SOURCE: Office of Technology Assessment, 1992.

limitations. This provision is particularly important

for individuals who are perceived to have stigmatic

conditions that are viewed negatively by society.

Examining genetics and the ADA from three

broad categories-genetic conditions, genetic predisposition, and carrier status-sheds some light on

how the ADA might interface with CF carrier

screening and future genetic tests (figure 1-13).

Genetic Conditions. Disability is defined only

according to the degree of impairment and how

severely the disability interferes with life activities,

with no distinction between those with genetic

origins and those without. A genetic condition that

does not cause substantial impairment might not

constitute a disability, unless others treat the person

as disabled. Thus, significant cosmetic disfigurements (e.g., from burns or neurofibromatosis) could

be classified as disabilities if public prejudices act to

limit the life opportunities of people who have them.

Congress and the courts have long recognized

disabilities of primary or partial genetic origin,

Figure l-13—Genetics and the Americans With Disabilities Act of 1990

SOURCE: Office of Technology Assessment, 1992.
Chapter I-Summary, Policy Issues, and Congressional Options ● 35

including Down syndrome, CF, muscular dystrophy,

epilepsy, diabetes, and arthritis.

Genetic Predisposition. ADA judges disability

not just by an objective measure of inability to

perform tasks, but also subjectively by the degree to

which the public makes the condition disabling

through misunderstanding or prejudice. This latter

definition might apply to individuals who are

asymptomatic but predicted to develop disease in the

future-if the public perceives them as having a

disability because they might or will get ill. Some

argue the ADA’s legislative history indicates genetic predisposition might be encompassed. One

Congressman stated during the 1990 debate over the

conference report that persons who are theoretically

at risk ‘‘may not be discriminated against simply

because they may not be qualified for a job

sometime in the future. ’ On the other hand, no

further discussion on the issue occurred,

Carrier Status. Case law and the ADA’s prohibition of discrimination generally hold that employment decisions must be based on reasonable medical

judgments that show the disability prevents the

individual from meeting legitimate performance

criteria, For carriers of recessive conditions such as

CF, sickle cell anemia, and Tay-Sachs, there is no

disability per se; the ADA appears not to cover

carriers, Such individuals are, however, at high risk

of having an affected child if their partners also carry

the trait and could be misunderstood to be affected

by the disease. Discrimination against carriers could

arguably constitute discrimination if based on a

perception of disability.

The Equal Employment Opportunity Commission (EEOC) Regulations. In 1991, EEOC promulgated regulations for implementing the ADA. The

regulations do not specifically prohibit discrimination against carriers or persons who are identified

presymptomatically for a late-onset genetic condition (e.g., adult polycystic kidney disease or Huntington disease)---despite the fact that the NIH/DOE

ELSI Working Group and the NIH/DOE Joint

Subcommittee on the Human Genome urged EEOC

to clearly protect these individuals. It its interpretive

guidance, EEOC notes “the definition of the term

‘impairment’ does not include characteristic predisposition to illness or disease. ” From EEOC’s

perspective, carriers are not encompassed by the

ADA’s provisions. With respect to individuals

diagnosed presymptomatically, EEOC concluded

that “such individuals are protected, either when

they develop a genetic disease that substantially

limits one or more of their major life activities, or

when an employer regards them as having a genetic

disease that substantially limits one or more of their

major life activities.

The Americans With Disabilities Act and Health

Insurance

The ADA also might prohibit discrimination

based on an employer’s fear of future disability in an

applicant’s family that would affect the individual’s

use of health insurance and time away from the job.

Nevertheless, the ADA does not speak to this point

directly, and so leaves open for future interpretation

whether employers may discriminate against carriers who are perceived as more likely to incur extra

costs due to illnesses that might occur in their future

children. The ADA specifically does not restrict

insurers, health care providers, or other benefit plan

administrators from carrying out existing underwriting practices based on risk classification. Nor does

the ADA make clear whether employers may

question individuals about their marital or reproductive plans prior to offering employment or enrollment in an insurance plan. Furthermore, after a

person is hired, ERISA-based, self-funded insurance

plans can alter benefits to exclude or limit coverage

for specific conditions; the ADA does not preempt

ERISA.

Quality Assurance of Clinical Laboratories

and DNA Test Kits

Quality assurance for CF carrier screening means

ensuring the safety and efficacy of the tests themselves, whether they are performed de novo in

clinical diagnostic laboratories or via test kits. The

quality of the laboratory’s performance affects the

quality of the counseling services. Ensuring that

consumers receive high-quality technical and professional service is the responsibility of providers,

under the shared oversight of the Federal Government, State and local governments, private entities

(including professional societies), and the courts.

The Clinical Laboratory Improvement

Amendments of 1988

Quality assurance to assess clinical laboratory

performance is still in flux, in large measure because

1967 legislation governing regulation of clinical

testing facilities was overhauled by Congress in
36 ● Cystic Fibrosis ati DNA Tests: Implications of Carrier Screening

1988 with enactment of the Clinical Laboratory

Improvement Amendments of 1988 (CLIA; Public

Law 100-578). CLIA subjects most clinical laboratories to an array of accrediting requirements:

qualifications for the laboratory director, standards

for the supervision of laboratory testing, qualifications for technical personnel, management requirements, and an acceptable quality control program.

CLIA authorizes the Health Care Financing Administration (HCFA) to police an estimated 300,000 to

600,000 physician, hospital, and freestanding laboratories to ensure they adhere to a comprehensive

quality assurance program. HCEA may impose

sanctions, if necessary.

CLIA clearly encompasses facilities performing

DNA-based, clinical diagnostic analyses. But, while

it details particular performance standards for several types of clinical diagnostic procedures, CLIA

does not specifically address DNA-based tests. This

lack of detailed directives for DNA-based diagnostics could be beneficial in the short-term, since the

field is rapidly changing.

State Authorities. CLIA does not preclude States

from regulating and licensing facilities within certain guidelines. After a pilot study, for example, the

California State Department of Health Services

intends to seek approval for State-specific licensing

laws and regulations for DNA and cytogenetic

laboratories. Similarly, New York has regulated

clinical laboratories since 1961, and has established

a genetics quality assurance program that includes

requirements for licensing personnel, licensing facilities, laboratory performance standards, and DNAbased proficiency testing. Nevertheless, the principal State role in quality assurance for clinical

facilities is licensure and certification of medical and

clinical personnel, which are the sole provinces of

States.

The Role of Private Organizations. While CLIA

clearly expands the Federal role in clinical laboratory oversight, the law continues to permit, subject

to DHHS approval, the involvement of other parties

in regulating laboratory practices. Private organizations, including the Joint Commission on Accreditation of Health Care Organizations, may continue to

accredit facilities. Private professional societies will

likely have the greatest impact in the area of

proficiency testing, one component of accreditation.

Efforts by CORN and its regional networks, ASHG,

and the College of American Pathologists (CAP)

stand at the forefront of developing proficiency tests

for DNA-based diagnostics.

In 1989, CAP established a committee to develop

appropriate guidelines for all clinical tests involving

DNA probes or other molecular biological techniques. The CAP committee has administered two

DNA-based proficiency testing pilot programs, although their focus was not genetic disorders. CORN,

which receives Federal funding and has been involved in quality assurance of genetics facilities

since 1985, sponsored a DNA-based genetic test

proficiency pilot of 20 laboratories in 1990. The

Southeastern region has a regional proficiency

testing program, and will be enlarging its planned

second survey into a national test, to be completed

in 1992; this effort includes CF mutation analysis.

Full proficiency testing for DNA-based genetic

diagnostics is planned by 1994. CORN and ASHG

have liaisons with the others’ efforts, and a joint

ASHG/CAP DNA-based proficiency testing pilot

for genetic diseases commenced in 1992.

Proficiency testing is widely viewed as a key

measure of quality assurance. It can provide a

reliable and identifiable benchmark to assess perPhoto credit: Genetics & IVF/Institute

Facilities that perform DNA-based diagnostic tests (e.g.,

CF mutation analysis) are subject to the Clinical Laboratory

Improvements Amendments of 1988.
Chapter I-Summary, Policy Issues, and Congressional Options ● 37

formance . In the past, professional societies’ involvement in proficiency testing to ensure laboratory quality have predominated, and this situation is

likely to continue. Cooperation among each of the

groups will be essential, as professional-societybased programs could affect proficiency testing for

CF mutations (and other DNA tests) long before

HCFA proposes proficiency testing rules under

CLIA.

Regulation of DNA Test Kits

Increased use of CF mutation assays for carrier

detection will depend, in part, on the development

and availability of prepackaged kits. At least two

companies-one in the United States and one in the

United Kingdom-are testing such kits and anticipate their availability in 1 to 2 years. Before

marketing of the kits can occur, however, the U.S.

Food and Drug Administration (FDA) must ensure

the safety and efficacy of genetic diagnostic test kits,

such as those under development for CF mutations.

Since genetic diagnostic kits fall within the definition of devices, the extent to which CF mutation

kits-or other DNA-based genetic test kits—

become available will depend on FDA regulation of

devices during development, testing, production,

distribution, and use.

FDA’s regulatory options range from registering

an item’s presence in the United States and periodically inspecting facilities to ensure good manufacturing practices, to setting performance and labeling

requirements, to premarket review of a device. The

agency also may engage in postmarketing surveillance to identify ineffective or dangerous devices. It

may ban devices it deems unacceptable. Specific

regulation depends on whether FDA classifies the

device as Class I, H, or III, with Class III devices

receiving the most stringent review.

Since no FDA-approved, DNA-based genetic

diagnostic test kit comparable to those being developed for CF carrier analysis exists, it is difficult to

predict the ultimate regulatory status of such kits.

Preliminary indications are they will be regulated as

Class III devices. In response to recent legislation

and ongoing congressional concern, FDA appears to

be increasing medical device regulation and postmarketing surveillance. If increased FDA scrutiny

extends to DNA-based diagnostic test kits, developers can expect more stringent regulation of these

products than of previous non-DNA-based genetic

test kits. Increased regulation to provide greater

Photo credit: Tony J. Beugelsdijk, Los Alamos National Laboratory

Automated robotic system used in DNA analysis at Los

Alamos National Laboratory.

assurance of safety and efficacy might, in turn, slow

routine CF carrier screening.

Automation

The extent to which costs for CF carrier tests

decline depends, in part, on automation. Instrumentation will be especially crucial to the development

of batteries of tests for multiple genetic disorders.

Moreover, compared to most routine clinical tests,

current DNA-based CF carrier assays are labor

intensive.

Over the past few years, private industry and U.S.

national laboratories have developed several instruments that increase the speed and volume of routine

DNA diagnostic procedures. Goals for improved

instrumentation for DNA analyses stem, in part,

from the importance of rapid techniques to the

Human Genome Project. Spin-off technologies from

DNA mapping and sequencing appear amenable to

applications for clinical diagnostics.

Currently, all but one step of what generally

constitutes DNA diagnosis is automated or involves

instrumentation under development. Most components of DNA analysis, however, are automated as

individual units; efforts under way seek to coordinate sequential steps. Some machines are not faster

than humans, but they can standardize the procedures and decrease human error.

Clearly, the crucial steps in DNA-based CF

carrier assays are, or can be, automated. Advances in
38 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

instrumentation indicate that automated, rapid carrier screening for CF---or other genetic conditions—

is already technologically feasible. OTA finds the

field of DNA automation is advancing at a pace that

suggests entirely automated DNA diagnosis can be

realized in the next few years.

Costs and Cost-Effectiveness

Perhaps the least examined facet of CF carrier

screening is cost. Data for parts of OTA’s analysis

were often lacking and assumptions had to be made.

Unlike the seven preceding factors, which in many

cases will generically affect utilization of DNAbased tests for disorders other than CF, findings that

pertain to cost-effectiveness do not extend beyond

CF carrier screening-although the approach used in

this report could be applied to screening with other

genetic tests.

While economic analyses can inform decisions

surrounding resource allocation and access to genetic screening, they have limits. In the context of

public policy and genetics, the 1983 President’s

Commission report on genetic screening articulates

solid guidance about the benefits and limits of

cost-effectiveness and cost-benefit analyses: These

analytical approaches are tools to be used within an

overall policy framework, not solely as a method of

making or avoiding judgment. There is no intimation in OTA’s analysis that something that saves or

costs money is more or less desirable from a welfare

standpoint.

Cost of Cystic Fibrosis

The cost of any illness is the answer to the

hypothetical question: If the disease disappeared and

everything else held constant, how many more

dollars would be available to the economy? Many

elements are needed to answer this question, but

broadly speaking they fall into two categories:

information about direct medical costs associated

with CF and nonmedical direct costs related to the

disease (i.e., family caregiving time).

Direct medical expenses for CF include costs of

hospitalization, outpatient care, physical therapy,

and drugs. These costs are not the same for everyone

with the disease (table 1-7). Clinical symptoms of

CF vary widely, although broad divisions in its

severity can be drawn. Some individuals require

only one inpatient visit every 2 years or so; others

Table 1-7—Annual Cost of Medical Care

for Cystic Fibrosis Patients

Treatment Milda Moderate Severe

Acute treatment

Antibiotics. . . . . . . . . . . . . . $ 2,000b

IV supplies. . . . . . . . . . . . . 300

Hospitalization. . . . . . . . . . 3,500

Miscellaneous. . . . . . . . . . . 100

Total cost acute. . . . . . . . . 5,900

Chronic management

Visits to CF Center. . . . . . . 600

Medications. , . . . . . . . . . . . 2,000

Total cost chronic. . . . . . . . 2,600

Total cost acute and

chronic treatment. . . . . . 8,500

$6,000

500

14,000

200

20,700

800

3,000

3,800

24,500

$12,000

900

28,000

400

41,300

1,200

4,000

5,200

46,500

have problems so severe as to require four or more

hospitalizations per year. Similar variation exists for

other medical expenses. Overall, taking these several factors into account, average annual medical

expenses for CF patients are estimated at $10,000.

Assuming a median life expectancy in 1990 of 28

years the present value of lifetime medical expenses

is approximately $146,430 (1990 dollars using a 5

percent discount rate).

The main nonmedical direct cost associated with

CF is parental time beyond the time required for a

child without the illness. CF centers estimate that

parents often must spend 2 hours per day on therapy

for a child with CF. In addition, parents lose time

from work when the person falls ill. Time is also

spent on physician and clinic visits. OTA uses an

estimate of 938 hours per year of extra caregiving to

a person with CF, which is generally provided by

family members. Assuming an estimated domestic/

nursing wage of $10 per hour, the present value of

CF-related lifetimedical direct costs is $139,744

(1990 dollars using a 5 percent discount rate).
Chapter 1--Summary, Policy Issues, and Congressional Options ● 39

Table 1-8-Costs for Cystic Fibrosis Carrier Tests

At Selected Facilities

Institution Price per sample

Baylor College of Medicine. . . . . . . . . . . . . . . . . $55 or 200

Boston University. . . . . . . . . . . . . . . . . . . . . . . . . 170

Collaborative Research, Inc.. . . . . . . . . . . . . . . . 173

Cornell University Medical Center. . . . . . . . . . . . 75

GeneScreen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Genetics & IVF Institute. . . . . . . . . . . . . . . . . . . . 225

Hahnemann University. . . . . . . . . . . . . . . . . . . . . 225

Hospital of the University of Pennsylvania. . . . . 150

Integrated Genetics. . . . . . . . . . . . . . . . . . . . . . . 150

Johns Hopkins University Hospital. . . . . . . . . . . 270

Mayo Medical Laboratories. . . . . . . . . . . . . . . . . 200

St. Vincent’s Medical Center. . . . . . . . . . . . . . . . 150

University of Minnesota. . . . . . . . . . . . . . . . . . . . 136

University of North Carolina. . . . . . . . . . . . . . . . . 150

Vivigen, Inc.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 to 220

SOURCES: office of Technology Assessment, 1992, and M.V. Pauly,

“Cost-Effectiveness of Screening for Cystic Fibrosis,” contract

document prepared for the U.S. Congress, Office of Technology Assessment, August 1991.

Cost of Cystic Fibrosis Mutation Analysis

Since CF is the most common, life-shortening,

recessive disorder among Caucasians in the United

States, commercial interest in the test is high.

Currently, at least six commercial companies perform DNA-based CF mutation analyses, as do at

least 40 university and hospital laboratories. Table

1-8 presents data on test charges for several private

and public facilities; the average price per sample is

about $170. With increased volume of tests and

automation, however, many predict the cost per CF

mutation assay will decrease, OTA uses a cost per

test of $100 because the analysis focuses on the

potential future of large-scale CF carrier screening

and presumes economies of scale will apply.

Indirectly related to cost-effectiveness, but directly related to how much CF mutation analysis will

cost in the future, is the issue of patents, licensing,

and royalty fees for genetic diagnostics. A patent is

pending for the CF gene, for example. Similarly,

royalty licenses must be paid for the process—the

polymerase chain reaction, or PCR—by which CF

mutation analysis is performed. Thus, royalty licensing fees will be reflected in costs of the tests to

consumers. Currently, debate is increasing on the

issue of intellectual property protection and the

Human Genome Project. A resolution of this controversy, if any, will affect costs of DNA-based

diagnostic tests and hence cost-effectiveness of

screening for genetic disorders.

Costs and Cost-Effectiveness of Carrier

Screening for Cystic Fibrosis

Data about the cost of screening large numbers of

individuals for CF carrier status do not exist. In

estimating the cost of carrier screening for CF, OTA

included costs of the CF mutation analyses, chorionic villus sampling for fetal testing, and costs for

pretest education and post-test counseling. Taken

together, these costs were analyzed in the context of

several scenarios for preconception screening of

women (and possibly their partners) and prenatal

screening of pregnant women (and if necessary their

partners and the fetus).

Regardless of the strategy or scale, CF carrier

mutation analysis provides information to an individual about his or her likelihood of having a child

with CF should the partner also be a carrier. Hence,

at its core, a cost-effectiveness analysis of CF carrier

screening involves assumptions about reproductive

behavior. A base case was established for the

following six variables:

●

●

●

●

●

●

80 percent of women elect screening,

85 percent sensitivity of the CF mutation assay,

8.4 percent of +/+ couples are infertile,

10 percent of +/+ fertile couples choose not to

conceive,

90 percent of +/+ fertile couples conceive, and

100 percent use prenatal testing, and

100 percent of CF-affected pregnancies detected are terminated.

As alternatives, other assumptions were made for

several additional scenarios by varying the factors in

turn (or combination) to yield a series of costeffectiveness estimates. In evaluating costs and

savings, changes in behavior were considered only

for +/+ couples, and costs and savings were calculated for a hypothetical population of 100,000

eligible women (or couples). The economic costs

include costs associated with CF carrier screening.

The economic savings include avoiding the direct

medical and nonmedical costs associated with having a child with CF. The base case and all scenarios

were then compared to costs in the absence of

screening.

One scenario, for example, assumed 50 percent of

women chose to participate, another assumed all

individuals elected screening. Another screened the

woman and man simultaneously, rather than screening the man only when the woman was positive.
40 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Photo credit: Robyn Nishimi

Others used 50 percent as the frequency of affected

pregnancies terminated. Overall, whether CF carrier

screening can be paid for on a population basis

through savings accrued by avoiding CF-related

medical and caregiving costs depends on the assumptions used—including how many children people

will have, average CF medical costs, and average

time and cost devoted to caring for a child with CF,

as well as variations in reproductive behaviors, costs

of CF mutation analyses, and screening participation

rates.

Eight of 14 scenarios examined by OTA result in

a net cost over no screening. Under six cases,

however, CF carrier screening is cost-effective, but

most of these scenarios involve 100 percent participation, test sensitivity, or selective termination-all

unlikely to be realized in the near term, if ever.

Nevertheless, CF carrier screening can save money

compared to no screening even under less absolute

circumstances. The balance between net savings

versus net cost in nearly all scenarios is fine. How

many individuals participate in screening is relatively unimportant to cost-effectiveness, but it is

clear the frequency of affected pregnancies terminated and the assay’s price will ultimately affect this

balance.

WHAT IS THE ROLE OF

CONGRESS?

Speculation about the impact of a CF carrier test

on individuals and society has existed for years.

Today, that speculation is being transformed into

reality. In this report, OTA identifies eight factors

affecting implementation of CF carrier screening.

From the analysis of these factors, OTA concludes

that Congress could play a role in six broad policy

areas:

ll

●

●

●

●

Ž

●

genetics education and the public,

personnel,

genetics and discrimination,

clinical laboratory and medical device regulation,

instrumentation, and

integration of DNA assays into clinical practice.

Genetics Education and the Public

For people to make informed decisions about

whether CF mutation assays would be useful to

them, they must understand what CF is, know what

carrier status means, and have some understanding

of the probabilistic nature of genetic tests. Beyond

comprehending technical information, the public

should also appreciate the positive and negative

social implications that could adhere. Better public

education would also mean fewer total counseling

hours would be needed.

Mechanisms by which Congress can generally

improve science and education in the United States

were assessed in a separate OTA report,12 Federal

efforts specifically targeted to educating the public

about human genetics are diffuse, but do exist. If

Congress determines that increased genetics educaI I Congess ~so plays a role ti ~ additio~ policy issue raised by CF carrier screening and the development of otier genetic tes~i.e., he~~ ~

access. As mentioned, however, access to CF carrier tests, and services related to them, is no different-and inextricably linked-to the broad issue of

health care reform in the United States, a topic beyond the scope of this report.

12 U.S. ConHess, office of ‘IkchnoIogy Assessment, Educuring Scientists and Engineers: Grade School to Grad School, OTA-SET-377

(Washington DC: U.S. Government Printing Office, June 1988).
Chapter 1-Summary, Policy Issues, and Congressional Options ● 41

tion is a priority, it could urge interagency coordination and/or appropriate increased funds. In particular, Congress could exploit three general avenues to

increase public education about genetics: schoolbased science education, patient education, and

widespread public appeal.

Existing agencies and programs have some efforts

related to public education in genetics, each serving

different purposes. These efforts can serve as the

foundation for new initiatives. The National Institutes of Health/U.S. Department of Energy’s Ethical, Legal, and Social Issues Programs of the Human

Genome Project, for example, have awarded grants

that target each of the avenues just described,

including curriculum development, science teacher

education, evaluation of improved means to deliver

genetic information to patients, and a mass media

production that will be available through public

television. If Congress concludes that ELSI Programs should increase their attention to public

education, it could direct them to seek and award a

greater number of grants focused on this issue. In

doing so, Congress could direct that a greater

proportion of such awards be made with existing

funds, at the expense of other areas. Or, Congress

could direct that more than the expected 5 percent set

aside from the fiscal year 1993 Human Genome

Project appropriation be devoted to the ELSI Programs-at the expense of the scientfic and technical

components—and that the increased funds be allocated to public education grants. Finally, Congress

could increase the ELSI Programs’ funding specifically for public education.

The National Science Foundation serves as the

lead Federal agency for science education, particularly teacher education and training. Thus, with

respect to specifically enhancing public knowledge

through school-based science education, Congress

could encourage NSF--directly through appropriations or indirectly through oversight—to increase

attention to education in human genetics. Currently,

supplemental genetics education for K-12 teachers

is piecemeal; NSF has funded a few projects to train

high school and grade school teachers about genetics, but no nationwide effort exists.

The DHHS National Center for Education in

Maternal and Child Health serves as the Federal

repository for a wide range of materials related to

human clinical genetics—ranging from genetics

training manuals for social workers to patient

information pamphlets for a number of genetic

diseases; it once served as an active clearinghouse to

disseminate information about genetics nationwide.

Due to budgetary constraints, the center now functions more as a passive resource to provide information on request, rather than performing aggressive

outreach. Through oversight, Congress might judge

that the lost function of the center should be

reinstated, but it would need to recognize that

increased funds would be necessary to achieve this

goal.

Personnel

Several types of health care professionals perform

genetic counseling-master’s level genetic counselors, physicians, Ph.D.-level clinical geneticists,

nurses, and social workers. No coordinated Federal

training and education framework exists to serve all.

The Federal Government provides financial support

for education and training of certain health personnel

through Title VII and Title VIII of the Public Health

Service Act. Title VII provides education support to

the fields of medicine, osteopathy, dentistry, veterinary medicine, optometry, podiatry, public health,

and graduate programs in health administration. It

does so through grants and contracts to institutions,

and through loans to individuals. Title VIII focuses

primarily on advanced training of nurses. The MCH

block grant also supports some genetics-related

training and education.

If Congress determines that training of additional

genetics personnel-beyond those practicing or in

the pipelines essential to maintain quality care, it

could enact Legislation that amends Title VII or Title

VIII to include master’ s-level genetic counseling

programs. It could also encourage increased genetics

education for the other health professions encompassed by these acts. Grantees and contractors that

receive Title VII or Title VIII funds, for example,

might be required to increase genetics-related curriculum for all health professionals. Congress could

also increase appropriations under the MCH block

grant, or stipulate that States receiving MCH funds

earmark a designated level of State funds to education, training, or both.

Genetics education for those already practicing is

as important as genetics trainin g and education for

new health professionals. In part, the issue of

adequate services and professional capacity depends

on whether patients continue to receive genetic
42 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

services through specialized clinical settings, as

most do now, versus access through primary care,

community health, and public health settings. If the

nonspecialized clinical route becomes more common, it will require that existing genetic specialists

provide adequate genetics education to other practitioners in the U.S. health care system. Congress

could focus on two executive branch entities to

accelerate this provider-to-provider knowledge transfer. First, it could continue to encourage the NIH/

DOE ELSI Programs of the Human Genome Project

to fund grants for this purpose. Second, Congress

could enhance, through increased appropriations,

professional training and continuing education efforts under the MCH block grant.

Genetics and Discrimination

Concern about discrimination arises from new

capabilities to assess genetic information. This

concern currently focuses on the Americans With

Disabilities Act and subsequent rulemaking by the

U.S. Equal Employment Opportunity Commission.

First, as enacted, the ADA left open the question of

whether genetic predisposition to illness or carrier

status were covered as protected classes. In its final

rule, EEOC rejected the premise that genetic predisposition or carrier status are covered under the ADA

for employment purposes. Because some debate

exists as to the intent of Congress in this area,

Congress could revisit the issue to clarify its

intentions with respect to genetic and disability

discrimination under ADA. Many opine that litigation will ultimately define the scope of the ADA.

Second, ADA is silent on whether employers may

discriminate-for the purposes of hiring-against

individuals (e.g., CF carriers) who are perceived as

more likely to incur extra costs due to illnesses that

could occur in their future children. An OTA survey

of Fortune 500 companies and companies with 1,000

or more employees revealed that 9 percent of

employers surveyed account for dependents’ potential expenses when considering an individual’s

application. If Congress determines the potential

health insurance costs of an applicant’s dependent

should not be considered in hiring decisions, it could

signal its intent through legislation.

Finally, concerns about discrimin ation in insurance coverage and repercussions on health care

access arise in the era of new genetic tests, but

insurance regulation in the United States is largely

a matter for the States. Nevertheless, one aspect of

health insurance relates to both the ADA and Federal

law regarding employee benefits (i.e., the Employee

Retirement Income Security Act of 1974). The

number of individuals receiving health care coverage via ERISA-based, self-funded plans is increasing. Under ERISA, which preempts State insurance

law, any self-funded company can cap, modify, or

eliminate employees’ health care benefits for a

particular condition at any time, as long as the

company complies with the notice requirements in

the plan agreement. Such conditions are in no way

limited to genetic illnesses. Congress could prohibit

such actions, if it deems it necessary, by amending

ERISA, the ADA, or both.

Clinical Laboratory and Medical Device

Regulation

Congress has along legislative history in regulating clinical laboratories and medical devices. In the

past 4 years, Congress has moved twice—the

Clinical Laboratory Improvement Amendments of

1988 and the Safe Medical Devices Act of 1990

(SMDA)-to address perceived deficiencies in each

area. Absent additional action by Congress, the

regulatory framework for clinical laboratories and

medical devices will evolve from these two statutes.

Currently, the regulatory status for both is in flux, as

executive branch agencies only now are developing

specific rules and regulations.

If Congress believes the new DNA-based genetic

diagnostics require clinical laboratory quality assurance considerations beyond the 1988 legislation, it

could amend CLIA to specify criteria for DNA

assays. On the other hand, the field of clinical DNA

diagnostics is changing rapidly. Congress might

prefer to maintain the Health Care Financing Administration’s flexibility in adapting to these changes.

In that case, Congress could monitor HCFA’s

approach to DNA analyses through its oversight of

HCFA’s implementation of CLIA, generally.

With respect to medical devices, no FDAapproved DNA test kit for CF mutation analysis

exists, although kits are being tested with companies’ expectation of their availability in 1 to 2 years.

Congress can amend SMDA if it believes DNA test

kits constitute so novel a device that SMDA’s

provisions for premarket evaluation and postmarked

surveillance do not suffice. Evaluating FDA’s regulation of DNA diagnostics in the absence of a
Chapter I-Summary, Policy Issues, and Congressional Options ● 43

product could prove difficult, however, and so

Congress might prefer to take no action at this time.

Instrumentation

The ability to test quickly and accurately will be

crucial to inexpensive CF carrier screening. It will be

even more important if panels of genetic assays for

an array of disorders are to be developed. Currently,

all but one step of techniques used in DNA

diagnostic analysis are automated, but there is little

integration of the components. If Congress determines that the goal of quick, accurate batteries of

DNA tests is important, it could make such integration a Federal research priority under the Human

Genome Project by designating that certain levels of

appropriations be targeted to tailoring instrumentation and automation to DNA diagnostics. Currently,

the Human Genome Project serves as the primary

funding locus for developing instrumentation to

automate DNA analysis+chiefly through appropriations to U.S. national laboratories.

DNA Assays and Clinical Practice

In today’s social, economic, and legal climate,

OTA believes that, as a practical matter, a federally

funded or controlled program for population-based

CF carrier screening is not on the horizon. In the

1990s, CF mutation analysis could become routine,

but not likely as part of a unified, national program.

If Congress determines in the distant future that a

programmatic public health model for CF carrier

screening or other genetic conditions is necessary, it

can look to the National Genetic Diseases Act to

craft a population-based program. In 1992, the issue

at hand is: How, and to what extent, will CF carrier

tests—and other genetic tests in the pipeline—

integrate into contemporary medical practice?

Many perspectives on how CF carrier screening

should be implemented exist, including a socially

regulated program, a free market model, and a focus

on patient autonomy and choice. Those who support

a regulated framework in the fashion of a public

health model (e.g., newborn genetic screening)

believe public health’s historical use of institutional

mechanisms and social approaches is appropriate

and necessary for quality assurance and consumer

protection. Others take a dim view of a regulated

model for CF carrier screening because they believe

that consumers are best served by having CF carrier

tests available through general medical practice and

by providing them the opportunity to choose and

manage their own health care. They argue that

formal, government-sponsored structure translates

to regulated medicine, which they oppose, because

it can interfere with patient care.

No definitive way exists to determine when

providers should routinely inform people about the

availability of genetic tests, and in some respects,

Congress has less a role to play in this policy issue

than in the preceding five. Nevertheless, Congress

can influence when and how genetic tests are

integrated in two specific ways.

First, 2 years lapsed between identification of the

CF gene and its mutations and the initiation of

federally sponsored pilot studies to assess routine

CF carrier screening. Before other DNA-based tests

come on-line, Congress could encourage the genetic

services delivery and genetic research agencies of

the executive branch to coordinate efforts to develop

an institutional means to ensure evaluation of

genetic tests through federally sponsored consensus

conferences, workshops, and pilot projects (if necessary) prior to their being incorporated into routine

medical care. In doing so, concerns raised that CF

carrier screening is being rushed into practice might

be assuaged if future tests receive federally led,

timely evaluation. On the other hand, critics of

Federal intervention will continue to argue that

federally sanctioned efforts will slow access to tests

and information that some consumers would find

desirable.

Second, once a test becomes fully integrated into

clinical practice, Congress can direct the Agency for

Health Care Policy and Research to examine whether

practice guidelines for CF carrier screening, or other

genetic tests, are appropriate. Supporters of practice

guidelines believe they offer the potential to decrease malpractice claims, control health care costs,

improve quality, and generally influence the use of

a technology. Detractors argue such guidelines

differ little from professional statements, will increase malpractice claims, and suggest regulated

medicine.

PROSPECTS FOR THE FUTURE

Leaving aside the precise timing of routine CF

carrier screening, it is clear the number of DNAbased tests for genetic disorders and predispositions

will increase rapidly over the next decade, almost

certainly by an order of magnitude. OTA considers

it likely that the time available, if any, for debate and
44 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Photo credit: Office of Technology Assessment

The U.S. Human Genome Project, jointly funded by the

U.S. Department of Health and Human Services and the

U.S. Department of Energy is estimated to be a 15-year,

$3 billion project. As the project continues to unfold,

Congress will likely face policy issues stemming from both

the discovery of new information and applications of the

information.

discussion on dissemination and use of new genetic

tests will be compressed as pressure to use them

rises. Given this scenario, some of the policy

questions raised in this report extend beyond implications for CF carrier screening.

On one hand, CF carrier screening can be used to

construct a paradigm that describes a set of policy

issues for genetic tests to come. Access to health care

merits specific mention because it is repeatedly

raised as a concern tied to the increasing availability

of genetic information-i. e., will the new knowledge elucidated through the Human Genome Project

positively or negatively affect how Americans

obtain or retain health care coverage? Certain

additional themes will apply: ensuring clinical

laboratory competence, quality assurance of the

tests, maintainingg high-quality service delivery,

promoting public education, supporting provider

training, and safeguarding against discrimination

and stigmatization. Of course, as American policies

and politics change---or remain the same-the

approaches to address these issues might differ.

Another generic issue, but one likely to ignite

controversy with each new test, is the pace at which

the assay should be integrated into general medical

practice. Early use of CF mutation analysis is in the

obstetric and prenatal context, and this trend will

likely continue. As such, it serves as a good model

to ex amine the broader consequences of genetic

screening when this context is the chief avenue of a

test’s introduction. But experience with CF carrier

screening is less applicable for tests that detect adult,

late-onset genetic disorders (e.g., Huntington disease or familial breast cancer) or tests that predict

genetic predisposition to multifactorial conditions

(e.g., coronary artery disease, and, again, breast

cancer). This issue---how customs of care evolvecould decline as broad categories of predictive

genetic tests develop. It might not, however, because

every disease and how people perceive each—

differs.

One consideration for the future not fully explored

in this report is indirectly related to costeffectiveness, but directly related to how much CF

mutation analysis-and other diagnostic genetic

tests—will cost in the future. At issue are patents,

licensing, and royalty fees for both products (e.g.,

the CF gene, for which a patent is pending) and

processes (e.g., PCR, for which Roche Molecular

Systems holds the patent) that are important to

DNA-based diagnostics. Although automation appears likely to lower costs of DNA diagnostics,

intellectual property protection, the impact of which

cannot be fully assessed, to some extent might

counter lower prices realized by new instrumentation. Issues surrounding intellectual property, scientific exchange, commercial development, and the

Human Genome Project have existed since that

project’s outset. They continue to loom and might

need congressional attention if they become pressing. Witness, for example, the new debate surrounding patenting certain DNA sequences.

Certain factors related to CF carrier screening will

be less germane to analyzing the implications of

other emerging tests that assess genetic risks. In

particular, cost-effectiveness is a case-by-case matter. Likewise, the issue of making automation a
Chapter 1---Summary, Policy Issues, and Congressional Options ● 45

priority through Federal funding for instrumentation

research and development presumably will dissipate.

Finally, fundamental to consideration of CF

carrier screening is the issue of genetic counseling

and abortion. Prenatal screening will probably

comprise the largest portion of CF carrier assays, at

least initially. Thus, as with prenatal tests generally,

the extraordinary friction about abortion in this

country is inevitably linked to the implications of CF

carrier testing and screening, But as knowledge from

the Human Genome Project accumulates, so will the

number and definitiveness of genetic tests, and so

presumably the social, ethical, and political tension.

Some tests will be more likely than others to have

prenatal applications, but as long as utilization of the

new assays by pregnant women is possible, some

will opt for abortion.

While not explicitly overturning Roe v. Wade, the

1992 U.S. Supreme Court decision in Planned

Parenthood of Southeastern Pennsylvania v, Casey

means women’s access to legal abortions now turns

largely on State law. The decision appears to affirm

that women may choose to terminate pregnancies

prior to fetal viability, but States may make this

more difficult than it has been prior to the ruling. The

court’s ruling in the Pennsylvania case indicates

States may enact laws related to information delivery, waiting periods, services provision, and restrictions on public financing or use of public facilities,

as long as such laws do not present a substantial

obstacle to a woman’s choice. If Congress believes

States should be preempted from enacting such laws,

it could pass Federal legislation prohibiting State

restrictions in any of these areas.

As well, the 1991 U.S. Supreme Court decision in

Rust v. Sullivan upheld Federal regulations stating

that patients at clinics receiving certain Federal

funds (i.e., from Title X of the Public Health Service

Act) may not receive information about the option of

terminating a pregnancy at risk for a child with a

genetic disorder. In March 1992, an executive order

modified the original regulation and stated that such

information may be provided by a physician, although the legal standing of that order is in question.

The vast majority of practitioners providing services

in such clinics—nurses and genetic counselors—

still may not inform patients of this option. Congress

came close to rescinding the entire restriction when

a majority of Members of Congress voted to

Photo credit: Chip Moore

The U.S. Supreme Court

overturn the regulation in 1991. If Congress believes

nonphysician health care professionals should be

allowed to counsel patients about abortion following

diagnosis of fetal abnormalities, it could reexamine

the issue and enact an exception for counseling

related to genetic conditions or overturn the regulation entirely.

Nearly 10 years ago, the President’s Commission

for the Study of Ethical Problems in Medicine and

Biomedical and Behavioral Research concluded the

fundamental value of CF carrier screening lies in its

potential for providing people with information they

consider beneficial for autonomous reproductive

decisionmaking. CF carrier screening, however, is

not just about a person's future reproductive choices.

CF carrier screening represents the first of many

DNA-based tests to come and raises many issues.

Policy decisions made about it will reverberate far

beyond this specific case.
Chapter 2

Introduction
Contents

Page

TERMINOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

RECENT HISTORY OF HUMAN GENETICS AND PUBLIC POLICY . . . . . . . . . . . . . 51

U.S. Law and Genetic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51

The 1983 President’s Commission Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

The Human Genome Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

THE INTERESTED PARTIES: PRESSURES FOR AND AGAINST SCREENING . . . 56

Scientific and Clinical Tensions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Social Pressures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

THE OTA ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . 61

OTA Surveys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Scope and Organization of This Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

CHAPTER 2 REFERENCES.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .63

Boxes

2-A. Eugenics at the Turn of the Century . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

2-B. Genetic Services: Federal-State Partnership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

2-C. The 1975 National Research Council Report, ’’Genetic Screening:

Programs, principles, and Research” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

2-D. Genetic Screening and the Practice of Public Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Figures

2-1. Inheritance of Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

2-2. Chromosome 7 and the Cystic Fibrosis Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

2-3. Trends in the Number of Samples Screened for Cystic Fibrosis

Carrier Status, 1989-91 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61

Tables

2-1. History of Cystic Fibrosis: Selected Highlights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

2-2. Research Grants Funded by the Ethical, Legal, and Social Issues Program,

National Institutes of Health and U.S. Department of Energy (May 1991) . . . . . . . . . 55

2-3. Test Sensitivity and Risk of Child With Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . 59

2-4. Public Attitudes About Making Genetic Tests Available Through Physicians . . . . . . 62

2-5. Consumer Attitudes Toward Genetic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Chapter 2

Introduction

People want-expect-perfectly healthy babies.

When a child is born with a genetic condition,

parents suffer anxiety, endure anguish, and experience guilt: “This baby is sick because of us. ”

This report is about one of these inherited

conditions: cystic fibrosis (CF). CF is a lifeshortening disorder. It is a genetic condition—i.e.,

one that follows a clear pattern of inheritance in

families-and is the most common, lethal recessive

disorder in American Caucasians of European descent. Each year in the United States, about 1 in

2,500 babies is born with CF (10,35,47 )---i.e., about

1,700 to 2,000 babies with CF are born annually

(25). Approximately 1 in 9,600 Hispanic, 1 in 17,000

(9) to 19,000 (50) African American and 1 in 90,000

(50) Asian American newborns have CF.

Medicine has long recognized the consequences

of CF (table 2-1) on several organ systems, particularly the lungs and pancreas. Only recently, however, have scientists pinpointed the most common

change, or mutation, in the genetic material-DNA—

that accounts for the majority of CF cases (44,66,68).

Because CF is a recessive trait, a child with CF must

receive two mutant CF genes, one inherited from

each parent, who are CF ‘‘carriers, ’ but who do not

have the disorder (figure 2-l). Thus, while approximately 30,000 people in the United States have CF,

as many as 8 million people could be carriers of one

CF mutation. What are the implications of informing

this latter pool of individuals--a a subset of those

of reproductive age and younger-about tests that

reveal CF carrier status?

TERMINOLOGY

Human genetics, like all scientific disciplines, is

rife with jargon, and subtle distinctions in language

can matter a great deal. People, reports, or institutions rarely define terms of art in precisely the same

manner. To avoid confusion, OTA uses several

terms as follows.

OTA defines genetic testing as the use of specific

assays to determine the genetic status of individuals

already suspected to be at high risk for a particular

inherited condition. While any individual can be

Table 2-l—History of Cystic Fibrosis: Selected Highlights

1650. . . . . . . . . . . . .

1705. . . . . . . . . . . . .

1857. . . . . . . . . . . . .

1938. . . . . . . . . . . . .

1946. . . . . . . . . . . . .

1946. . . . . . . . . . . . .

1953. ......, . . . . .

1955. . . . . . . . . . . . .

1959. . . . . . . . . . . . .

1960 to present. . . .

1968. . . . . . . . . . . . .

1981 to 1983. . . . . .

1986. . . . . . . . . . . . .

1989. . . . . . . . . . . . .

1990. . . . . . . . . . . . .

1990. . . . . . . . . . . . .

1991 . . . . . . . . . . . . .

Literature refers to now characteristic CF pancreatic and lung symptoms

association with salty skin and early death.

A book of folk philosophy states that a salty taste means a child is bewitched.

The Almanac of Children’s Songs and Games, Switzerland, quotes from Middle

Ages: “Woe is the child who tastes salty from a kiss on the brow, for he is hexed,

and soon must die.”

First reported description of disease, calling it “cystic fibrosis of the pancreas.”

Antibiotics found effective for treating CF-related lung infection.

Inheritance pattern-autosomal recessive-suggested.

Sweat abnormality in CF first described.

First review of use of pancreatic enzymes to treat CF.

Safe and accurate way to diagnose CF, “sweat testing,” reported.

Accelerated improvement in survival.

Mechanism underlying CF-related male infertility demonstrated.

Basis for sweat abnormality (i.e., electrolyte transport problems) described.

CF gene localized to chromosome 7.

CF gene and its most common mutation identified.

CF mutation assays available from selected genetic laboratories, companies, and

medical centers.

CF mutation corrected in laboratory cells.

Functions of CF gene described.

SOURCE: Office of Technology Assessment, 1992, based on L.M. Taussig, Cystic Fibrosis (New York, NY:

Thieme-Stratton, Inc., 1984).

-49-
50 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 2-1—inheritance of Cystic Fibrosis The difference between testing and screening is

illuminated by considering a person contemplating

procreation. He or she could inquire about the

availability of an assay to determine the probability

that he or she could have a child affected with CF.

If there are no relatives with the disorder, the

SOURCE: Office of Technology Assessment, 1992.

considered ‘‘at high risk’ for a particular unknown

trait, and hence be “tested,” ‘ ‘at high risk” here

denotes the presence of a family history or clinical

symptoms. The terms genetic test, genetic assay,

and genetic analysis are used interchangeably to

mean the actual laboratory exarnination of samples.

Genetic screening usually uses the same assays

employed for genetic testing, but is distinguished

from genetic testing by its target population. OTA

uses the term ‘screening’ selectively. In this report,

it refers to analyzing samples from individuals

without a family history of the disorder, groups of

these individuals, or populations. Carrier screening for CF (or CF carrier screening), then, involves

performing tests on persons for whom no family

history of the disorder exists to determine whether

they have one normal and one aberrant copy of the

CF gene, but not the disorder (which results from

having two aberrant CF genes).1

Many individuals are CF carriers but do not have

a positive family history. In fact, 4 of 5 babies born

with CF each year-as many as 1,600---are cases

where there was no known family history for CF.

disease, a practitioner would ideally inform the

individual and his or her partner about CF carrier

assays and they might choose to be tested t o

determine if they are both carriers.

Genetic counseling is a clinical service that

includes providing an individual (and sometimes his

or her family) with information about heritable

conditions and their risks. When centered around

genetic testing and screening, it involves both

education and psychological counseling to convey

information about the ramifications of possible test

outcomes, prepare the client for possible positive or

negative analyses, and discuss actual test results.

Many types of health professionals perform genetic

counseling. OTA reserves the term genetic counselor for master’ s-level individuals certified (or

board-eligible) by the American Board of Medical

Genetics to clarify the discussions of the legal

distinctions in licensing and third-party reimbursement among the different types of practitioners. But,

OTA uses the term genetic counseling more generically to refer to the educational and informational

process that is performed by genetic specialists,

including physicians, Ph.D. clinical geneticists,

genetic counselors, nurses, and social workers.

OTA avoids using the term “program” in discussing CF carrier screening in the United States.

For many, the term connotes a formal public health

effort led or sanctioned by Federal, State, or local

governments. In analyzing CF carrier screening,

OTA’s premise is that large numbers of Americans

might be screened for their CF carrier status. OTA

remains neutral on whether the assays will be a

component of a fixed, regulated scheme or another

facet of general medical practice.

I In contrast, OTA uses the term CF screening (or screeningjiir CF) to mean screening individuals to diagnose the presenee or absence of the actual

disorder, in the absence of medical indications of the discxise or a family history of CF. Such screening usually involves newborns (ch. 3), but is rarely

done for CF except in Colorado and Wisconsin. CF testing of infants is common if a family history of the condition exists.
Chapter 2 Introduction . 51

Box 2-A—Eugenics At the Turn of the Century

Eugenics refers to processes or policies to either discourage or prevent reproduction by members of society

with ‘‘undesirable” heritable traits or to encourage or require procreation by individuals who have ‘‘desirable”

genetic characteristics. Put more broadly, it involves efforts that interfere with individuals’ reproductive choices in

order to attain a ‘‘societal’ goal. Drawing on roots developed by Francis Galton, a cousin of Charles Darwin, in

England in the late 1800s, eugenics movements flourished in the United States at the turn of the century.

Compulsory sterilization laws were an outgrowth of the U.S. eugenics movement. The Model Eugenics Act,

from which many States drafted their laws in the early 1900s, targeted institutionalized tuberculosis patients, people

who were blind or deaf, and chronic alcoholics among those who should be sterilized. In 1927, the U.S. Supreme

Court upheld the Commonwealth of Virginia’s sterilization law, Justice Oliver Wendell Holmes writing:

We have seen more than once that the public welfare may call upon the best citizens for their lives. It would be

strange if it could not call upon those who already sap the strength of the State for these lesser sacrifices, often not

felt to be such by those concerned, in order to prevent our being swamped with incompetence. . . . Three generations

of imbeciles are enough (16).

Despite the fact that compulsory sterilizations continued into the 1970s, the eugenics movement per se waned

in the United States during the 1930s, largely from distaste with Hitler’s embrace of eugenics. Wariness over past

abuses of genetic information led to the emphasis on nondirective genetic counseling in clinical practice.

Nevertheless, the legacy of eugenics—though by and large renounced-continues to color perceptions about

large-scale genetic screening, and thus to subtly influence decisions surrounding human genetics and public policy,

SOURCE: Office of Technology Assessment 1992, based on N.A. Hoi_ Proceed With Caution: Predicting Genetic Risks in the

Recombinant DNA Era (Baltimore, MD: The Johns Hopkins University Press, 1989); D.J. Kevles, In the Name of Eugenics

(Berkeley, CA: University of California Press, 1985); K.M. Ludmerer, Generics and American Society: A Historical Appraisal

(Baltimore, MD: The Johns Hopkins University Press, 1972); P, Reilly, Generics, Law, and Social Policy (Cambridge, MA: Harvard

University press, 1977); and P. Reilly, The Surgical Solurion (Baltimore, MD: The Johns Hopkins University Press, 1991).

RECENT HISTORY OF HUMAN

GENETICS AND PUBLIC POLICY

The science of human genetics is embedded in

this country’s consciousness, and has manifested

itself---vertly and covertly-in public policies

throughout U.S. history (box 2-A). Race and skin

color, for example, are genetically influenced, and

have played a direct role in official and unofficial

decisionmaking. In some respects, identifying carriers of CF mutations—invisible genetic characteristics—is just another twist in the history of genetics

and U.S. public policy, but one that has implications

for the majority population in this Nation.

To provide background and perspective for today’s

debate about CF carrier screening, this section

briefly describes watershed events in U.S. politics

and human genetics. Not intended to be comprehensive, it focuses on a few, discrete events in the 20th

century that place the questions raised by CF carrier

screening in context and help frame the issues and

options addressed by this report. The impact of

broader U.S. laws, such as Title VII of the Civil

Rights Act (42 U.S.C. 2000e) and the Americans

With Disabilities Act (Public Law 101-336; 42

U.S.C. 12101), are discussed elsewhere in the report.

U.S. Law and Genetic Disease

Most U.S. legislation related to genetic disease is

State law covering newborn screening (2,63,78,89).

During the 1970s, however, Congress enacted three

measures involving carrier screening for several

genetic conditions (Public Laws 92-294, 92-414,

and 94-278). Today, most State newborn screening

laws (and the programs and practices established by

them) operate, for the most part, unchallenged. In

contrast, the Federal Government’s role in public

health and genetics has changed historically.

In the late 1960s and early 1970s, sickle cell

anemia received prominent attention as a health

concern. The African American community felt that

sickle cell anemia was a neglected condition, with

little Federal research funding directed toward it. As

the debate progressed, Federal interest, along with

State interest, developed. President Nixon made an

appeal for an effort to combat sickle cell anemia in

his 1971 health address to Congress (39), and the

following year he signed into law the National
52 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Sickle Cell Anemia Control Act (Public Law 92-

294). While the act focused on detecting sickle cell

anemia, the mechanics of the test also identified

carriers for sickle cell. Later that year, Congress

moved a second time to enact legislation directed at

another genetic disease, ß-thalassemia, with the

National Cooley’s Anemia Control Act (Public Law

92-414).

Both programs represented a significant expansion of Federal support for nonresearch genetic

initiatives. Federal programs supported only State

efforts with voluntary participation, a measure

designed to defuse ongoing controversy over mandatory, coercive screening. And although the statutes’ intent was to reduce stigmatization of and

discrimination against carriers, these practices continued unabated (64).

In 1976, Congress amended the sickle cell legislation, broadening it to the National Sickle Cell

Anemia, Cooley’s Anemia, Tay-Sachs, and Genetic

Diseases Act (Public Law 94-278; hereinafter the

National Genetic Diseases Act). In doing so, it

expanded both the scope and authority of activities,

as well as the range of genetic disorders for which

Federal grants and contracts were awarded. The

legislation emphasized voluntary participation and

the use of proper guidelines for confidentiality of

results; it also stressed that genetic counseling for all

participants should be available-goals that experts

agree are desirable for CF carrier screening (18,54).

In 1978, Congress reauthorized the program, which

continued to provide funding for basic and applied

research, training, screening, counseling, and information and education programs (Public Law 95-

626).

In 1981, the role of the Federal Government in

genetic services, education, and training dramatically altered (61). Authorization for programs operated under the National Genetic Diseases Act was

replaced by the Maternal and Child Health Block

Grant (Public Law 97-35). No longer were Federal

funds for genetic services, professional training, and

public education programs guaranteed: The majority

of fund allocation decisions have since been left to

individual States. Programs for genetic services,

research, and professional training now compete

with other maternal and child health services (box

2-B). And while many States have responded with

State or regional programs, the reduced Federal role

led a presidentially appointed commission to voice

concern about the adequacy and effectiveness of

genetic services, education, and training (61).

While difiicult to quantify, decreased Federal

attention to genetic services, training, and education

might have left the country less than well prepared

to handle the rapid integration of molecular genetics

research into clinical practice. From the late 1970s

to the present, basic research in genetics has enjoyed

generous Federal sponsorship and returned the

dividend of increased knowledge about many genetic conditions. In contrast, Federal funds for

projects relating to genetic services show a steady

decline since 1981. These genetic services provide

the link to translate basic research developments into

clinical practice.

A void in Federal funding for genetic services

might have exacerbated at least one issue raised by

the prospect of routine CF carrier screening: the

inadequacy of training-related monies to ensure

sufficient genetic counseling services. Similarly,

decreased Federal spending for genetic services

likely contributed to the initial scrambling to fired

pilot studies for CF carrier screening (17,67). In

fact, it was left to the National Center for Human

Genome Research (NCHGR), National Institutes of

Health (NIH)---a research, not service, agency—to

step forward and coordinate clinical assessments of

genetic services for CF carrier screening (90).

In October 1991, NCHGR funded six 3-year

clinical assessment studies to examine education

and counseling issues related to CF carrier screening. The National Institute of Child Health and

Human Development and the National Center for

Nursing Research also funded one project each (53).

The Cystic Fibrosis Foundation, which took a lead

role in funding investigations to find the CF gene

and its mutations, declines to participate in any

decisions about pilot projects for CF carrier screening, saying its mission is not prevention, but

improving treatment and finding a cure (67).

The 1983 President’s Commission Report

In 1980, Congress created the President’s Commission for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research

(Public Law 95-622; 42 U.S.C. 300). Among the

topics Congress mandated that the Commission

examine was the ethical, social, and legal implications of genetic screening, counseling, and educa-
Chapter 2----introduction ● 53

Box 2-B-Genetic Services: Federal-State Partnership

Funding for genetic services derives from a medley of Federal and State sources, and varies greatly from State

to State. During the 1970s, genetic services enjoyed substantial Federal funding, in part through congressional

mandate. The Omnibus Budget Reconciliation Act of 1981 (Public Law 97-35), however, led to the consolidation

of genetic services funding-along with seven other programs—into the Maternal and Child Health (MCI-I) Block

Grant. Overall, funding for maternal and child health services was cut, and the responsibility for distributing the

monies and for providing services was passed to the States, which also had to begin using $3 in State funds for every

$4 of Federal money received. Prior to the block grant, no matching funds were required.

Under provisions of the MCH block grant, 85 percent of funds go directly to the States for maternal and child

health services. States must decide how to allocate the funds among a number of areas, such as general prenatal care,

infant nutritional supplementation, and other maternal and child health needs. MCH funds maybe used for health

care services, education, and administration. In fiscal year 1990, less than 2 percent of MCH funds were used by

States to support genetic services other than newborn screening.

In general, MCH funds account for a small portion of State genetic services. Under terms defined by the block

grant, each State decides whether or how much money to designate for genetic services. In 1990, 34 States used

MCH funds to support some aspect of general genetic services other than newborn screening, including

nonpatient-related activities such as administration and planning. In the majority of States, however, MCH funds

accounted for less than 25 percent of fiscal year 1990 funding for genetic services (51). In fiscal year 1990, MCH

funding for genetic services other than newborn screening totaled approximately $8 million; State funding

accounted for approximately $22 million (51).

Fifteen percent of the MCH block grant is administered as direct grants for Special Projects of Regional and

National Significance (SPRANS). SPRANS monies are grants for specific projects and are not given to each State.

SPRANS provides seed money for demonstration, or pilot, projects in a number of areas. After the demonstration

period ends, usually in 3 years, alternative funding must be found.

In fiscal year 1990, genetic services received about 9 percent of all SPRANS funds. When adjusted for

inflation, however, constant dollar funding for genetic services under SPRANS has decreased almost every year

since the block grant’s inception. Moreover, SPRANS support of genetic services has decreased born about 90

percent of the SPRANS genetic services budget in 1981 to about 66 percent in 1991. Initially, most of the SPRANS

genetic services budget established statewide genetics programs, with each State receiving seed money for at least

4 years. The last State received funding in 1990 (27). Other areas of genetic services delivery receiving SPRANS

support include ethnocultural projects to increase utilization of genetic services by undersexed populations;

psychosocial studies; and support groups for young adults and families. In fiscal year 1990, 16 States used

approximately $4 million from SPRANS grants to support demonstration projects in clinical genetic services other

than newborn screening (51). In fiscal year 1990, just over one-third of SPRANS’ genetic services budget went to

the regional networks and the Council of Regional Networks for Genetic Services (CORN) (27). CORN and the

regional networks-comprised of genetic service providers, public health personnel, and consumers-serve as

resources for communication and coordinate data collection and quality assurance, but do not provide direct services

to patients.

In addition to block grant and SPRANS awards, States also fund genetic services from other sources. In fiscal

year 1990, at least 26 States derived $46 million in genetic services funding exclusive of newborn screening from

provider in-kind and service charges, third-party reimbursement, grants, contracts, newborn screening fees, health

insurance surcharges, and mental health/mental retardation reds. For some States, such funding aCCOunts for mOSt

of their genetic services funding. For example, newborn screening fees generated 93 percent of genetic services

funding in Colorado and 86 percent in Michigan in fiscal year 1990. Similarly, prenatal screening service fees

accounted for more than 83 percent of the genetic services budget in California in fiscal year 1990 (51).

All States, the District of Columbia, and Puerto Rico coordinate genetic services statewide; nearly half

experienced a decrease in funding for genetic services from fiscal years 1988 through 1991 (51). Individual State

genetic service programs face yearly uncertainty about how much—if any-funding they will receive, which makes

planning difficult. As general knowledge and public awareness about genetic diseases continues to emerge out of

the Human Genome Project, uncertainty in genetic services funding will be increasingly problematic.

SOURCE: Office of Techology Assessment, 1992.
54 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 2-C—The 1975 National Research Council Report,

“Genetic Screening: Programs, Principles, and Research”

In response to a letter from the American Society of Human Genetics, the National Research Council (NRC) of the

National Academy of Sciences convened a committee in 1972 specifically to analyze neonatal screening for

phenylketonuria and generally to assess the relation between genetics and preventive medicine. In particular, the

committee was charged with addressing the questions: To what degree has genetics played a part in thinking about and

practice of disease prevention? How should this relationship be fostered and extended?

Key recommendations of the committee were that participation be left to the discretion of the person tested and that

information obtained as a result of a test not be made available to others except with the consent of the patient The

committee also advised that professionals responsible for screening programs be aware of and regularly assess

potentially damaging effects of screening, including invasion of privacy, breach of confidentiality, civil rights violations,

and psychological effects from being labeled a genetic carrier. Principles described in the report still underlay genetic

screening and testing today.

The NRC report was not ubutuated by the Federal Government, but it was supported with Federal funds from the

National Science Foundation. It made a critical impact in shaping future discussions, such as the 1983 President’s

commission report, Screening and Counseling for Genetic Conditions: The Ethical, Social, and Legal Implications of

Genetic Screening, Counseling, and Education Programs.

SOURCE: Offuce of Technology Assessment 1992, based on Committee for the Study of Inborn Errors of Metabolism, National Researeh

Council Genetic Screening: Programs, Principles, and Research (Washingtom DC: National Academy of Sciences, 1975).

tion programs. In 1983, the Commission published The Human Genome Project

the results of its deliberations (61).

In carefully weighing the advantages and disadvantages of applications of advances in medical

genetics, the Commission found, on the whole, that

these advances have greatly enhanced health and

well-being (62). Drawing on the literature (55) (box

2-C) and public hearings, the Commission reached

15 conclusions, including recommendations about

the confidentiality of genetic information and mandatory versus voluntary screening (61).

The Commission’s report on genetic screening is

noteworthy for its examination of past experience

with screening programs (e.g., for Tay-Sachs disease, sickle cell anemia, and phenylketonuria) and

its prescience in using CF carrier screening as a

specific case study. The Comrnission’s analysis

explored ethical aspects of genetic screening in

anticipation of issues it predicted would be raised by

large-scale carrier screening for CF. It concluded

that the fundamental value of CF carrier screening

lies in its potential for providing people with

information they consider beneficial for autonomous

reproductive decisionmaking (61,62). Nine years

ago, the Commission identified some of the same

controversies being discussed today.

As the 21st century approaches, Congress and the

executive branch have made a commitment to

support scientific efforts to determine the location

on the DNA of all genes in the human body (as has

been done for CF)--in short, to map the human

genome. The Human Genome Project is estimated to

be a 15-year, $3 billion project. It has been

undertaken with the expectation that enhanced

knowledge about genetic disorders, increased understanding of gene-environment interactions, and improved genetic diagnoses can advance therapies for

the 4,000 or so currently recognized genetic conditions; a premise supported by the fact that even prior

to the Human Genome Project, advances in medical

genetics have guided the development of new

treatment strategies and incrementally improved the

management of some genetic conditions over the

years (22,23).

In many respects, the Human Genome Project

served as the catalyst for congressional interest in

this OTA assessment. Despite scientifuc and technological promises of the project, fears have been

raised about how information gained from it—such

as identification of CF mutations—will be used

(37,52,56,57,80). These concerns will involve policy decisions for Congress.
Chapter 2---Introduction ● 55

To address gaps in knowledge and perhaps million (3 percent). Fiscal year 1992 spending is

forecast the social consequences of the Human targeted at $1.77 million (3 percent) (26). NIH-ELSI

Genome Project, NIH and the Department of Energy spending for fiscal years 1990 and 1991 was $1.56

(DOE) each fund an Ethical, Legal, and Social Issues million (2.6 percent) and $4.04 million (4.6 percent),

(ELSI) Program. Funds for each agency’s ELSI respectively. For fiscal year 1992, NIH-ELSI aims to

effort derive from 3 to 5 percent of appropriations set spend 5 percent of the NCHGR appropriation ($4.98

aside from the total genome initiative budget. In million) (45). Table 2-2 lists the types of efforts that

fiscal year 1991, DOE’s ELSI spending was $1.44 have been funded to date by the ELSI program.

Table 2-2—Research Grants Funded by the Ethical, Legal, and Social Issues

Program, National Institutes of Health and U.S. Department of Energy (May 1991)

Source Description

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

DOE. . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NlH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

Project to prepare 50 selected science teachers per year for 3 years to become State resource teachers in human

genetics. Workshops will also update and expand curriculum materials.

Project to examine legal protections of confidentiality y of genetic information and to study the availabilit y of and need to

collect genetic data to plan public health service programs.

Study to assess the significance of discrimination directed against individuals and family members because of real or

perceived differences in their genetic constitution.

Project to survey ethical attitudes toward the medical applications of genetic information and to conduct a legal study of

confidentiality of genetic data.

Report examining the current funding mechanisms in the biological and biomedical sciences of major Federal agencies

and private organizations to determine the impact of funding on the ability to recruit and retain young investigators.

Eight-part television series, “The Secret of Life.”

Curriculum development module and instructional activities, “Mapping and Sequencing the Human Genome: Science,

Ethics, and Public Policy,” for first-year high school biology students.

Conference and laboratory workshop for nonscientists drawn from four groups: public policy makers, civic leaders,

program officers of health-related foundations, and science journalists.

Conference: “Justice and the Human Genome Project.”

Study, including public education and participation, to determine the impact of the Human Genome Project on women and

to identity ways of avoiding or reducing potential gender injustice.

Historical analysis of the relevance of eugenics to genomics for the specific case of cancer theory and policy.

Study to examine the ethical and legal implications of genetic information on understanding health, normality, and disease

causation.

Project to develop a human molecular genetics curriculum module for honors, main-stream, and low-achieving high

school students and adults in a continuing education program. (Cofunded with the NIH Center for Research Resources.)

Series of projects to update and inspire secondary school science teachers in genome technologies and their implications,

including newsletter for educators, “hands on” demonstrations to the public and at schools, and workshops.

National survey of public knowledge and perceptions of genetic testing and the Human Genome Project. (Cofunded with

the National Science Foundation (NSF).)

Survey of physicians’ and master’ s-level genetic counselors’ knowledge of and attitudes toward genetic testing. Survey

and interview of commercial interests in and impact on human genetics research.

U.S.-Canadian survey of geneticists’, genetic counselors’, and genetic clinic patients’ views on a variety of situations in

genetics that pose ethical dilemmas. A separate grant involves a survey of geneticists from 34 additional nations about

the same situations.

Sociological study exploring the meaning of human genetics in popular culture (e.g., fiction, film, news accounts) to

understand lay interpretations of genetic concepts.

Comparison of feminist, medical, and bioethical analyses of impact of genetic testing on parent-child relationships.

(Cofunded with NSF.)

Study of the concept of genetic susceptibility y and the basis and limits of privacy of genetic information about individuals.

Ethnographic study of the impact of genome research on the social organization of biological science.

Report on professional standards for forensic DNA typing. (Cofunded with NSF, Federal Bureau of Investigation.)

DNA sequencing of mitochondrial DNA to define the technical and statistical limits of this approach to human identification

applications (e.g., identifying victims of accidents, natural disasters, and wars; reuniting separated families; investigating

claims of identity; and aiding criminal investigations).

(Continued on next page)
56 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 2-2—Research Grants Funded by the Ethical, Legal, and Social Issues

Program, National Institutes of Health and U.S. Department of Energy (May 1991)-(Continued)

Source Description

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. . . . . . . . . .

NIH. , . . . . . . . .

NIB. . . . . . . . . .

NIB. . . . . . . . . .

NIB. . . . . . . . . .

NIB. . . . . . . . . .

NIB. . . . . . . . . .

NIH/DOE. . . . .

NIH/DOE. . . . .

NIH/DOE. . . . .

NIH/DOE. . . . .

NIH/DOE. . . . .

Study of the impact of genetic testing and counseling on medicine and the doctor-patient relationship.

Paradigm analysis to develop a comprehensive and systematic framework to resolve ethical issues raised by genomic

information in clinical genetics.

Study of the historical and social impact of amniocentesis.

Study examining historical case studies to examine the potential risks of stigmatization associated with genetic testing,

screening, and diagnosis.

Interdisciplinary study of the implications for insurance of increasing information from the Human Genome Project.

Study of the impact of genetics on access to health care.

Historical analysis of the impact of the genetics of human leukocyte antigens on criminology and the genetics of race.

Training manual and communication materials to train geneti conunselors to, in turn, conduct courses for primary care

providers.

Intensive short course for scientists and bioethicists on the ethical, legal, and social implications of the Human Genome

Project.

Education workshop series for State legislators and other State officials.

Public lecture series on the ethical, legal, and social implications of the Human Genome Project.

Forum for genetic disease support groups on the Human Genome Project and its ethical, legal, and social implications.

Eight CF pilot screening projects (six by National Center for Human Genorne Research, Ethical, Legal, and Social Issues

Program, and one each by the National Center for Nursing Research and National Institute of Child Health and Human

Development.)

Conferences: “Strategies for Documentation of Research on the Human Genome,” “Human Genome Workshop: Ethics,

Law, and Social Policy, ““bgal and Ethical Issues Raised by the Human Genome Project,” “A Legal Research Agenda

for the Human Genome Initiative,“ “The Genetic Prism: Understanding Health and Responsibility,” “Ethics, Values,

Professional Responsibilities,“ “Biotechnology and the Diagnosis of Genetic Disease,” “Testing for Germ Line p53

Mutations in Cancer Families,” “Human Genome Research in an Interdependent World,” “Ethical and Legal Implications

of Genetic Testing,” “Computers, Freedom, and Privacy, “ “The Human Genome Project: A Choices and Challenges

Forum,” “A Conference on Human Genorne Research Implications,” and “Genetic Factors in Crime: Findings, Uses, and

Implications.”

Conference: “Genetics, Religion, and Ethics.”

Project to examine issues of privacy, stigma and discrimination, particularity as they relate to culturally diverse

groups--both those who have and have not used genetic services.

Study investigating newborn genetic screening programs and policies governing State-sponsored genetic screening.

Minority populations’ access to and use of genetic services will be examined, including the nature of services available

to rural populations.

Television documentary, “The Future of Medicine.”

Report addressing a variet y of issues presented by the rapid proliferation of genetic tests capable of predicting future

disease.

SOURCE: Office of Technology Assessment, 1992.

THE INTERESTED PARTIES:

PRESSURES FOR AND

AGAINST SCREENING

Why is carrier screening for CF a controversy?

Experts agree that persons with a family history of

CF should have the opportunity to avail themselves

of the new, DNA-based tests. No one espouses

mandatory screening. Who opposes voluntary screening, and on what grounds? Who supports CF carrier

screening, and why? Do past experiences with

large-scale genetic screening (e.g., maternal serum

alpha-fetoprotein, sickle cell, or Tay-Sachs) provide

a framework to answer questions raised by routine

CF carrier screening? What is the role of genetics in

public health (box 2-D)?

Many parties have a stake in resolving questions

raised by our increased understanding of human

genetic disease, including CF. These stakeholders

include consumers, health care providers, and commercial ventures. Also weighing in on the evaluation

of the technical, legal, ethical, and economic considerations are experts and professional societies in

each of these fields. This section briefly describes

the tensions that have arisen and identifies areas
Chapter 2--introduction . 57

Box 2-D---Genetic Screening and the Practice of Public Health

In some respects, friction over routine carrier screening for CF reflects different notions of public health and

its interaction with genetics. What is public health, today? How do genetic testing and screening for CF fit in its

practice? Do they fit at all? Does the evolving practice of clinical genetics challenge many common assumptions

about the limitations on, and aims of, public health authorities?

Public health is a dynamic field, and its history records struggles over the limits of its mandate. Public health

attempts to prevent disease, prolong life, promote physical health through sanitation of the environment, control

contagious infections, educate individuals and whole populations about health, and organize medical services for

the early diagnosis and preventive treatment of disease. Since it can involve social machinery to ensure maintenance

of health (59,69), such institutional mechanisms might sooner or later violate-or be perceived to violate---private

beliefs, private property, or the prerogatives of other institutions (73). Today, some public health initiatives, such

as quarantine or immunization, are mandatory. Compulsory components, however, are only a narrow slice of what

constitutes the practice of public health. There is nothing inherently coercive or mandatory about public health per

se: Witness, for example, public education about drug abuse, sanitation, or voluntary cholesterol or blood pressure

screening.

Debates surrounding public health issues, such as the spread of infectious disease, often involve an adversarial

model focused largely on balancing individual rights against community rights, on the assumption that the two are

in conflict (1,60). For public health issues like genetic testing and screening, however, individual interests might

be in harmony with public interests, and thus cooperative models of individual and governmental action (3,34,59)

could be more appropriate. On the one hand, who better to make the choice of whether to conceive a child with a

genetic disorder than the individuals who will both gain from and provide support to the child. At the same time,

as the Human Genome Project project continues to identify genetic risks that everyone faces in procreation, genetic

diagnosis and counseling becomes an aspect of personal health for the entire community-and hence perhaps

governmental action.

Nevertheless, disputes about the role of public health practices in genetics arise and often adopt polemic tones.

The balance between individual freedom, individual responsibility, and government responsibility for health is

especially delicate in areas such as carrier screening for CF. If examined from the view of public health measures

to control disease, CF and other genetic illnesses are fundamentally different from infectious disease. Unlike

familiar public health measures such as vaccination or sanitation policies, CF carrier screening does nothing to

protect individuals from the causes of disease, nor does it directly improve personal health. CF carrier screening

conveys information about future scenarios—i.e., the potential of CF occurring in one’s offspring, not oneself.

Viewed negatively from this perspective, some maintain that public health and genetics equate with eugenic

motives. Still others take a dim view of a public health role for CF carrier screening, not because of eugenic

overtones, but because they believe that consumers are best served by having CF carrier tests available through

general medical practice. They argue that formal effort translates to regulated medicine, which they oppose.

Balanced against these perspectives, however, are beliefs of others that public health currently centers on

identifying, educating, and counseling individuals and populations about achieving good health. From this

perspective, genetic screening falls squarely beneath the public health rubric, which should play an important and

appropriate role in CF carrier identification. These voices argue that there is nothing inherently eugenic about the

role of public health in genetics. To the contrary, many believe public health’s historical tradition with institutional

mechanisms and social approaches is appropriate and necessary for quality assurance and consumer protection.

It is easy to see how a formal CF carrier screening policy could be perceived as a form of eugenics if it were

assumed that all persons found to be carriers would, or should, act to prevent the birth of a child with a genetic

condition. Thus, while some maintain that such is not the case and that the public health goal met by routine CF

carrier screening is to provide information and options, others assert that early diagnosis or reducing incidence of

genetic illness on a population basis is also an implicit goal. In any case, whether information about carrier status

affects the incidence of CF ultimately depends on how individuals use information provided by screening, and

reducing incidence of the disorder might not be a goal per se of carrier screening, but could be a consequence.

SOURCE: Office of Technology Assessment, 1992.
58 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 2-2-Chromosome 7 and the

Cystic Fibrosis Gene

P

In humans, DNA is associated with protein, in bundles called

chromosomes. Each chromosome contains many genes, but only

the chromosomes-which can be ordered in pairs by their size

and shape-are microscopically identifiable. Humans have 46

chromosomes: 1 pair of sex chromosomes (two X chromosomes

for females; an X and a Y for males) and 22 pairs of autosomes.

In 1986, scientists discovered that the CF gene was on chromosome 7. Left: Chromosome 7, as visualized by light microscopy.

Right: Schematic of chromosome 7; arrow denotes location of CF

gene on the long arm of the chromosome.

SOURCE: Office of Technology Assessment, 1992.

about which concern has been expressed. Subsequent chapters elaborate on and analyze these issues.

Scientific and Clinical Tensions

Elucidation of the location of the CF gene and the

most common mutation leading to the condition—

commonly referred to as delta F508 (DF508) (figure

2-2) (44,66,68)-has been quickly followed by a

widely available, direct-DNA assay for carrier

testing and screening. Using today’s technology, it

is usually a one-time test that can inform an

individual whether he or she carries a CF mutation

and could thus pass it to his or her offspring (who

would be affected if it also received a CF mutation

from the other parent). In theory, carrier screening

for CF could encompass 100 to 125 million Americans of reproductive age, but will probably involve

significantly fewer numbers.

Routine CF carrier screening will likely integrate

into medicine in the reproductive context first—

chiefly obstetric/prenatal, but also preconceptional.

A focus on pregnant women, however, is not without

controversy (13,20,48,49). Some have concerns

about abortion, and some have reservations that

prenatal testing negatively shapes perceptions of

pregnancy, disability, and women (48,49). Nevertheless, based on the annual number of births (4.2

million) (31,88) and spontaneous abortions (an

estimated 1.8 million) (31), there are approximately

6.0 million pregnancies per year for which CF carrier

screening might be performed. Twenty-four percent

of women giving birth receive no prenatal care until

the third trimester (88), however, so CF carrier

screening in the obstetric/prenatal context would .

involve, at most, 10 million2 men and women per

year, depending on who is screened. Followup

carrier screening that focused on relatives of people

identified as carriers initially, rather than mass

screening, also significantly reduces the number

who theoretically must be screened to identify a

majority of carriers (24).

The current test, however, leaves ambiguity when

results are negative. About 1 in 25 Caucasians carry

a CF mutation, but the DF508 test identifies only 70

to 80 percent of actual CF carriers3 in this population, depending on a person’s ethnicity (30,47).

More than 170 additional genetic alterations in the

gene also cause CF—i.e., a person with CF can have

the same mutation on his or her chromosomes or two

different mutations. Assays using DF508 plus 6 to 12

other CF mutations (DF508+6-12) identify 85 to 90

percent of CF carriers, depending on the population

being screened (21,58). (In Ashkenazic Jews,

DF508+6 identifies nearly 95 percent of carriers

(71).) Thus, a negative test result does not guarantee

that a person is not a carrier. He or she could carry

one of the rare CF mutations that was not assayed

and hence still be a carrier. For a test that detects 85

percent of carriers, about 1 in 165 individuals who

test negative using DF508+6-12 will have an undetected mutation; at 90 percent sensitivity, 1 in 246

individuals who test negative will be a carrier (47).

2 ~S fiwe d~s not ~ccomt for tie es~ted 2.4 million ~efie couples who me &ying to conceive md might be interested in ~ carrier screening

(would increase overall figure). Nor does it estimate the number of men and women not involved in a pregnancy (would increase), the number of

individuals involved in more than one conception per year (would decrease), or those who might have been screened during a previous pregnancy (would

decrease).

s It should be emphasized that the AF508 DNA-based test is not 70 to 80 percent accurate. Evidence indicates that the test per se is specitlc, and

that DNA tests yield accuracy greater than 99 percent (1 1,46). That is, if the AF508 mutation is present in the individual’s genome, the test detects it

absent laboratory error. Like all diagnostic tests, a certain number of false positive or false negatives can arise during the course of testing. Quality control

and quality assurance, discussed in chapter 5, are designed to reduce this number to a small figure.
Chapter 2Antroduction . 59

Table 2-3-Test Sensitivity and Risk of Child

With Cystic Fibrosis

Couples at 1 in 4 risk Affected fetuses

Percent with each pregnancy in first pregnancy

mutations

detected Actual i-/+b +/h ./-b Actual Detectable Missed

Photo credit: IG Laboratories, Inc.

85 160 115.6 40.8 3.6 40 28.9 11.1

90 160 129.6 28.8 1.6 40 32.4 7.6

95 160 144.4 15.2 0.4 40 36.1 3.9

DNA analysis for the most common mutation responsible

for CF, DF508. A dot indicates the individual has a DF508

mutation. The absence of a dot means the person does not

have a DF508 mutation, but he or she could carry one of

the other 170+ CF mutations.

Couples where each partner is a carrier are

sometimes referred to as carrier couples, or couples

who are positive/positive (+/+). For these couples,

the chance of having a child with CF is 1 in 4 for each

pregnancy. If the CF test detected 100 percent of

mutations, a couple in which one partner is positive

and one negative (+/-) would not beat risk of bearing

a child with CF. Tests to detect 170+ mutations are

impractical, however, and even if they were feasible,

not all CF mutations have been identified. Using

DF508+6- 12 means that for +/-couples, the negative

partner could carry one of the rare mutations that the

assay is not structured to detect. Couples where one

partner is a carrier and the other’s result is negative

might misunderstand that their reduced risk is not

zero risk.

For example, if 100,000 random couples were

screened, 160 couples would be identified as +/+ if

the test were 100 percent sensitive; one-fourth of

frost-time pregnanices for these 160 couples (i.e., 40)

would be expected to result in CF-affected fetuses.

Instead, at 85 percent sensitivity, about 116 couples

will be identified as +/+ and with each pregnancy

have a 1 in 4 risk of a child with CF. Results for

93,315 will be -/-, and about 6,569 couples will have

+/- results. In fact, approximately 41 of the 6,569

couples with +/- results are at 1 in 4 risk of bearing

a child with CF in each pregnancy, while the

remaining 6,528 have no risk-but these two groups

cannot be distinguished with an 85 percent test

sensitivity (6,47).

About 4 of the 93,315 couples with -/- test results

are also actually at 1 in 4 risk with each pregnancy

of having a child with CF. Thus, of the theoretical

160 +/+ couples, 116 are dectable and 44 are not

when the test is 85 percent sensitive. In other words,

if all 100,000 couples experience a first-time pregnancy, 40 fetuses with CF are expected. But with an

a per 100,000 couples.

b Test results.

SOURCE: A.L. Beaudet, Howard Hughes Medical Institute, Houston, TX,

personal communication, March 1992.

85 percent sensitive test, 29 are detectable and 11

missed. If the assay elucidates 95 percent of carriers,

144 of 160 couples would be detected. In this case,

if all 100,000 couples experience a frost-time pregnancy, only 4 couples at 1 in 4 risk of having a child

with CF would be missed (table 2-3) (4,6).

With a test that detects 85 percent of CF carriers,

a couple with a +/- result has approximately a 1 in

661 risk of having an affected child with each

pregnancy (compared to a general population frequency of about 1 in 2,500). At a 95 percent

detection rate, a couple whose result is +/- faces a 1

in 1,964 risk of an newborn with CF with each

pregnancy (47). When the test detects a greater

proportion of mutations, +/- couples can be told with

greater confidence that their risk of having a child

with CF is more remote; hence they might be less

anxious about uncertainty. Couples who both test

negative, while not having zero risk, would have a 1

in 109,200 risk of an affected child with each

pregnancy (85 percent sensitivity) (47).

Some scientists, clinicians, and organizations

argue that even achieving detection levels of 90 to 95

percent is insufficient to justify routine CF carrier

screening-that other requirements must be met

(4,7,12,18,29,32,41,54,93). They assert that CF

mutation tests are appropriate only for testing

individuals or families with a known history of CF

or in pilot projects. Another view holds that individuals should not be advised about CF carrier screening, but for those who actively seek it and who

receive sufficient education and counseling, screening is acceptable (42). Others, while also advocating

pilot studies, believe the current state-of-the-art is

sufficient for the test to now be offered routinely to

persons of unknown risk during the course of general

or obstetric/prenatal care (5,12,14,33,65,70). The

latter proponents argue that consumers should be

informed about the test and be given an opportunity
60 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

to choose whether to take it or not. Related to the

issue of informing individuals about CF carrier

assays is concern on the part of some physicians that

withholding information about their availability

leaves them vulnerable to malpractice suits.

Social Pressures

Science is so much a part of society that it is no

longer useful, or helpful, to consider its impact in

isolation (36). While CF carrier screening is first a

question of science, it is also a question of personal

values (28). Not surprisingly, then, pressures for and

against CF carrier screening do not center solely on

scientific issues. Intertwined are matters of law,

ethics, and economics. Compelling arguments that

assess, weigh, and consider these factors are being

made for and against routine CF carrier screening,

This section briefly touches on the social pressures

involved; the ensuing chapters analyze them in

greater detail.

For some questions, the debate is highly charged,

emotional, and divisive+. g., prenatal testing and

the option of abortion. The extraordinary tensions in

the United States about abortion affect, to a certain

extent, the analysis of the implications of CF carrier

testing and screening. A couple where both partners

are positive for DF508+6-12 can undergo prenatal

testing to determine whether the fetus will have CF.

The Cystic Fibrosis Foundation, for example, divorces itself from the CF carrier screening debate,

and the abortion issue apparently played a major role

in this policy (67). Nevertheless, although abortion

tinges the debate, reproductive aspects of CF carrier

screening encompass broader choices, including

avoiding conception, seeking adoption, or choosing

artificial insemination by donor.

Another concern expressed by opponents of CF

carrier screening is that market pressures will drive

widespread use of tests before the potential for

discrimination or stigmatization by other individuals or institutions (e.g., employers and insurers) is

assessed (8,15,93). This view contends that commercialization and advertising will lead some to opt

for screening without fully realizing the implications

of, for example, insurance considerations. On the

other hand, patient demand is a major element of

market forces. Thus, some point out that commercialization of genetic tests is not the factor responsible for increased interest in genetic assays, but rather

Photo credit: Office of Tehnology Assessment

Five-year plan for the U.S. Human Genome Project, jointly

funded by the U.S. Department of Health and Human

Services and the U.S. Department of Energy.

that commercialization is the response to public

demand.

Because the price to consumers for CF tests

averages about $170 per test, opponents also raise

questions about costs. While some clients can afford

out-of-pocket payments for CF carrier assays, issues

of access arise for those who cannot pay but wish to

use the tests. Moreover, even with less expensive

tests, CF assays, like all diagnostic tests, are subject

to limitations defined by laboratory quality control

and quality assurance. Thus, what standards should

prevail? How should quality be monitored? Finally,

opponents of widespread CF carrier screening ask:

How can the limited genetic services delivery

system in the United States handle the swell of CF

carrier screening cases, let alone cases of other

genetic conditions arising from increased knowledge from the Human Genome Project? These

voices express concern on both quantitative and

qualitative fronts: that inadequate numbers of personnel exist (93) and that optimal methods for
Chapter 2--4ntroduction ● 61

educating and counseling related to CF carrier

screening need definition for those personnel who

are available (40).

Figure 2-3-Trends in the Number of Samples

Screened for Cystic Fibrosis Carrier Status, 1989-91

10 ~ I

Those who advocate CF carrier tests for use

beyond affected families are no less concerned about

the issues just raised. Rather, proponents argue on

other legal and ethical grounds that screening should

move forward and individuals routinely informed

about the assays so they can voluntarily choose to

avail themselves of the tests (12,33,65,70). They

assert that the tests are sensitive enough for current

use and will, like most tests, continually improve.

Since 80 percent of babies born with CF are to

couples with no previous family history (42), these

voices believe that failing to inform patients now

about the availability of CF carrier assays denies

people the opportunity to make personal choices

about their reproductive futures, either prospectively---e.g., by avoiding conception, choosing to adopt,

or using artificial insemination by donor--or by

using prenatal testing to determine whether a fetus is

affected.

THE OTA ASSESSMENT

For years, scientists, clinicians, lawyers, ethicists,

and policymakers theorized about the potential

consequences that increased knowledge of human

genetics would bring. In the early 1990s, CF

mutation tests move the debate from the theoretical

to the practical. With this report, OTA assesses both

the current technical capability of direct, DNAbased tests to detect mutations in the CF gene and

what this capability means for individuals and

society.

For some, the key question hovering over routine

carrier screening for CF is if, not when. For others,

the debate has shifted to when, not if. Without

making judgment on its appropriateness or inappropriateness, OTA finds that the matter of CF carrier

screening in the United States is one of when, not if.

The expansion in the number of tests for CF carrier

status will likely continue (figure 2-3); OTA estimates that as many as 63,000 individuals could be

screened for their CF carrier status in 1992. A rapid

upward trend is not entirely unexpected, however,

given the nascent stage of the technology’s move4 This number is based on a canvas of 41 facilities performing CF mutation analysis (30 responding) and tests performed in federally and privately

funded pilot studies. It underestimates the number of individuals who will be informed about CF carrier scr*g, since: not all who are informed agree

(o screening, standards of care will evolve, and not all facilities responded.
62 ● cystic Fibrosis and DNA Tests: Implications of Carrier Screening

OTA Surveys

In collecting information for this assessment,

OTA found specific details were needed to answer

questions about two areas covered by the report:

●

●

What are the attitudes of genetic counselors and

nurses in genetics toward CF carrier testing and

screening? To date, what have been their

experiences with CF mutation analyses? What

are their current caseloads and what changes do

they expect with routine CF carrier screening?

Have their patients had difficulties with health

insurance coverage due to results from genetic

tests?

What are the attitudes and policies of health

insurers toward genetic testing and screening

for CF carriers? Do these differ by provider

type, i.e., commercial health insurers, Blue

Cross/Blue Shield (BC/BS) plans, and health

maintenance organizations (HMOs)? How does

genetic information, including information from

genetic assays, affect underwriting? What role

do they envision for genetic tests in their future

business practices?

OTA addressed these questions by conducting

mail surveys. First, OTA surveyed the June 1991

members of the National Society of Genetic Counselors and the International Society of Nurses in

Genetics. OTA focused on genetic counselors and

nurses in genetics to avoid duplication with, and to

compare its results to, other surveys of medical and

clinical geneticists (38,91). A separate background

paper describes this survey’s approach and presents

data OTA collected that are not directly related to CF

carrier screening (86).

Second, to address questions related to practices

and attitudes toward genetic information for individual health insurance policies or medically underwritten groups, OTA sent tailored questionnaires to three

survey populations: medical directors of commercial insurers; medical directors and chief underwriters of all BC/BS plans; and medical directors at the

50 largest HMOs, largest HMO within a State, or

largest by HMO model type. This report summarizes

these data and examines their implications for the

policy issues surrounding carrier screening for CF.

As with the results from the genetic counselors/

nurses in genetics survey, a separate OTA background paper describes this survey’s methods and

results in greater detail (87).

Table 2-4-Public Attitudes About Making Genetic

Tests Available Through Physicians

Question: If there were genetic tests that would tell a person

whether they or their children would be likely to have

serious or fatal genetic diseases, would you approve or

disapprove of making those tests available through a

physician?

Paralleling the paucity of information about

counselors’ and insurers’ attitudes toward genetic

testing and screening is our lack of knowledge about

how consumers view these practices today. A new

OTA survey of Americans’ attitudes toward genetic

testing and screening was not feasible for this report,

however. Nor was a comparative analysis possible

of the views of the general population versus

CF-affected individuals or families. Other studies,

however, have surveyed certain aspects of consumer

attitudes toward prenatal diagnosis of CF (43,92)

and neonatal and carrier screening for CF (19).

A 1986 OTA telephone survey (77) of a national

probability sample of adult Americans reported that

about 9 of 10 Americans approved of making genetic

testing available through doctors (table 2-4). Furthermore, 83 percent of respondents reported they

would take a genetic test before having children if

such a test would tell them whether their children

would probably inherit a fatal genetic disease (table

2-5). Survey respondents were not, however, specifically questioned about CF.

An independent survey in 1990 queried Americans about their attitudes toward genetic tests in a

different manner, but found overall public opinion

toward them was favorable. Sixty-six percent of

respondents believed ‘‘genetic screening will do

more good than harm. Even when informed as part

of a question that treatment was impossible for most

serious genetic conditions despite the availability of

prenatal diagnosis, 69 percent said they would want

prenatal testing if they (or their partner) were

pregnant (72).
Chapter 2---Introduction ● 63

Table 2-5—Consumer Attitudes Toward Genetic Tests

Question: If genetic tests become available that would indicate

whether or not it was likely that your children would

inherit a fatal genetic disease, would you personally

take such a test before having children or not?

Percent a

Would take test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Would not take test. . . . . . . . . . . . . . . . . . . . . . . . . . 15

Not sure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Scope and Organization of This Report

As mentioned earlier, the primary focus of this

report is the implications of routine carrier screening

for CF. Secondarily, the report analyzes the appropriateness of using CF as a model for policy

decisions raised by tests for other genetic conditions:

To what extent is there an algorithm that describes

the policy implications of the broad array of current

and potential genetic tests? Where possible, the

report analyzes how experiences with CF carrier

screening can be used to construct a generic set of

policy issues. Conversely, where concerns and

possible solutions for CF carrier screening are

inappropriate or less relevant, the report identifies

these areas.

To provide a perspective on CF, medical information about the disease—its diagnosis, its therapy,

and its prognosis-is presented in chapter 3. To set

the stage for the legal, economic, social, and policy

analyses of CF carrier screening, chapter 4 describes

the genetics of CF: It covers the technical basis

for—and limitations of—DNA tests for CF mutations. Chapters 5 through 9 analyze five key aspects

of CF mutation analysis: quality assurance, education and counseling facets, financing, social and

legal dimensions of discrimination issues, and costs

and cost-effectiveness. CF carrier screening programs in the United Kingdom are described in

chapter 10, which also analyzes if lessons learned

from these efforts can aid decisionmaking in the

United States. Appendixes A and B describe the

international epidemiology of CF mutations and

case studies of other carrier screening efforts,

respectively.

This report does not present an ethical analysis per

se of the implications of routine CF carrier screening

because the fundamental principles identified in the

1983 President’s Commission report remain unchanged (61,62). And although the boundary of this

report encompasses carrier screening for CF, previous OTA reports analyze other issues related to new

genetic technologies, including: genetic monitoring

and screening in the workplace, the implications of

the Human Genome Project, the commercial development of tests for human genetic disorders, human

gene therapy, forensic uses of DNA tests, and

technologies to detect heritable mutations (74-77,

79,80,83-85). Finally, detailed analyses of allied

issues, such as safety and efficacy of amniocentesis,

prenatal care and pregnancy management (78),

termination of pregnancy, and assisted conception

(81,82) are beyond the scope of this report.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10,

CHAPTER 2 REFERENCES

Adelman, C. S,, ‘‘The Constitutionality of Mandatory

Genetic Screening Statutes, ” Case Western Reserve

hWJ Review 31:897-948, 1981.

Andrews, L. B., State Laws and Regulations Governing Newborn Screening (Chicago, IL: American Bar

Foundation, 1985).

Bayer, R., Private Acts, Social Consequences: AIDS

and the Politics of Public Health (New Yorh NY:

The Free Press, 1989).

Beaudet, A. L., “Invited Editorial: Carrier Screening

for Cystic Fibrosis,” American Journal of Human

Genetics 47:603-605, 1990.

Beaudet, A. L., Howard Hughes Medical Institute,

Houston, TX, remarks at the 8th International Congress of Human Genetics, Washington, DC, October

1991.

Beaudet, A. L., Howard Hughes Medical Institute,

Houston, TX, personal communication, February

1992.

Biesecker, L., Bowles-Biesecker, B., Collins, F., et

al., “General Population Screening for Cystic Fibrosis Is Premature, ’ American Journal of Human

Genetics 50:438-439, 1992.

Billings, P. R., “Mutation Analysis in Cystic Fibrosis, ’ New England Journal of Medicine 323:62,

1990.

Boat, T.F., “Cystic Fibrosis,” Textbook of Respiratory Medicine, J,F. Murray and J.A, Nadel (eds.)

(Philadelphia, PA: W.B. Saunders, 1988).

Boat, TF., Welsh, M. J., and Beaudet, A. L., “Cystic

Fibrosis, ’ The Metabolic Basis of Inherited Disease,

C.R. Scriver, A.L. Beaudet, W.S. Sly, et al. (eds.)

(New York, NY: McGraw Hill, 1989).
64 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

11.

12.

13.

14.

15.

16.

17.

18.

19.

20,

21.

22.

23.

24.

25.

26.

Boehm, C. D., and Kazazian, H. H., Jr., “Prenatal

Diagnosis by DNA Analysis,” The Unborn Patient:

Prenatal Diagnosis and Treatment, 2nd cd., M. Il.

Harrison, M.S. Golbus, and R.A. Filly (eds.) (Philadelphia, PA: W.B. Saunders Co., 1991).

Booth, W., “Genetic Screening for Cystic Fibrosis

Provokes Anxious Debate,” Washington Post, Aug.

10, 1991, p. A3.

Bowles-Biesecker, B., University of Michigan Medical Center, Ann Arbor, MI, personal communication,

December 1991.

Brock, D., “Population Screening for Cystic Fibrosis,’ American Journal of Human Genetics 47:164-

165, 1990.

Brown, D., “Individual ‘Genetic Privacy’ Seen as

Threatened,” Washington Post, Oct. 20, 1991.

Buck v. Bell, 274 U.S. 200 (1927).

Caskey, C. T., Howard Hughes Medical Institute,

Houston, TX, personal communication and remarks

at “The Impact of Human Molecular Genetics on

Society,’ Banbury Center, Cold Spring Harbor, NY,

November 1990.

Caskey, C. T., Kaback, M. M., and Beaudet, A. L.,

“The American Society of Human Genetics Statement on Cystic Fibrosis Screening, ’ American

Journal of Human Genetics 46;393, 1990.

Cobb, E., Holloway, S., Elton, R., et al., “What Do

Young People Think About Screening for Cystic

Fibrosis?,” Journal of Medical Genetics 28;322-

324, 1991.

Collins, F. S., Howard Hughes Medical Institute, Ann

Arbor, MI, personal communication, January 1992.

Collins, F. S,, “Cystic Fibrosis: Molecular Biology

and Therapeutic Implications, ” Science 256:774-

779, 1992.

Cook-Deegan, R. M., Gene Quest: Science, PoZitics,

and the Human Genome Project4 Prepublication

Drafi for Scholars (Washington, DC: Georgetown

University National Reference Center for Bioethics

Literature, 1991).

Cook-Deegan, R. M., ‘‘The Human Genome Project:

The Formation of Federal Policies in the United

States, 1986- 1990,” Biomedical Politics, K.E. Hanna

(cd.) (Washington, DC: National Academy Press,

1991).

Cox, TK., and Chakravarti, A., “Detection of Cystic

Fibrosis Gene Carriers: Comparison of Two Screening Strategies by Simulations, American Journal of

Human Genetics 49(Supp.):327, 1991.

Cunningham, J. C., and Taussig, L. M., A Guide to

Cystic Fibrosis for Parents and Children (Bethesda,

MD: Cystic Fibrosis Foundation, 1989).

Drell, D., Human Genome Program, Office of Health

and Environmental Research, U.S. Department of

Energy, Germantown, MD, personal communication, November 1991.

27.

28.

29.

30.

31.

32.

33.

34.

35,

36.

37.

38.

39.

40.

41.

Duffy, E., Genetic Services Branch, Maternal and

Child Health Bureau, U.S. Department of Health and

Human Services, Rockville, MD, personal communication, February 1992.

Eddy, D. M., “How To Think About Screening,”

Common Screening Tests, D.M. Eddy (cd.) (Philadelphia, PA: American College of Physicians, 1991).

Elias, S., Annas, G. J., and Simpson, J. L., “Carrier

Screening for Cystic Fibrosis: Implications for Obstetric and Gynecologic Practice, ’ American Journal

of Obstetrics and Gynecology 164:1077-1083, 1991,

Estivill, X., Casals, T, Mortal, N., et al., “AF508

Gene Deletion in Cystic Fibrosis in Southern Europe,” L.uncet 2:1404, 1989.

Forrest, J. D., Gold, R. B., and Kenney, A-M., The

Need, Availability and Financing of Reproductive

Health Services (New York, NY: The Alan Guttmacher Institute, 1989).

Gilbert, F., “Is Population Screening for Cystic

Fibrosis Appropriate Now?,” American Journal of

Human Genetics 46:394-395, 1990.

Gilbert, F., Cornell University Medical College,

“Cystic Fibrosis Carrier Screening in the General

Population as We Enter 1992, ” personal communication, January 1992.

Gosti.n, L, O,, Curran, W.J., and Clarlq M., “The Case

Against Compulsory Case Finding in Controlling

AIDS-Testing, Screening and Reporting,” American Journal of Law and A4edicine 12;7-53, 1987.

Hammond, K. B., Abman, S.H., Sokol, R.J., et al,,

“Efficacy of Statewide Neonatal Screening for

Cystic Fibrosis by Assay of Trypsinogen Concentrations,’ New England Journal of Medicine 325:769-

774, 1991.

Hanna, K. E., ‘‘ Conclusions,’ Biomedical Politics,

K.E. Hanna (cd.) (Washington, DC: National Academy Press, 1991).

Holtzrnan, N. A., Proceed With Caution: Predicting

Genetic Risks in the Recombinant DNA Era (Baltimore, MD: The Johns Hopkins University Press,

1989).

Holtzrnan, N. A., Johns Hopkins University, Baltimore, MD, remarks before the Ethical, hgal, and

Social Issues Committee of the National Center for

Human Genome Research, National Institutes of

Health, Arlington, VA, January 1991.

Hubbard, R., and Henifen,M.S.,‘‘Genetic Screening

of Prospective Parents and of Workers: Some Scientific and Social Issues,” International Journal of

Health Services 15:231-251, 1985.

Juengst, E. T,, National Center for Human Genome

Research, National Institutes of Health, personal

communication, December 1991.

Kabac~ M., “Should Cystic Fibrosis Testing Be

Available to the General Population?,” Perspectives

in Genetic Counseling 12(1):5, 1990.
Chapter 2--4ntroduction . 65

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

Kaback, M., University of California, San Diego, San

Diego, CA, remarks at ‘‘Cystic Fibrosis Counseling:

A Two-Day Workshop for Genetic Counselors, ”

Sarah Lawrence College, Bronxville, NY, January

1992.

Kaback, M., Zippin, D., Boyd, P., et al., “Attitudes

Toward Prenatal Diagnosis of Cystic Fibrosis Among

Parents of Affected Children, ” Cystic Fibrosis:

Horizons. Proceedings of the 9th International

cystic Fibrosis congress, D. Lawson (cd.) (New

York, NY: John Wiley & Sons Inc., 1984).

Kerem, B.-S., Rommens, J. M., Buchanan, J. A., et al.,

‘‘Identification of the Cystic Fibrosis Gene: Genetic

Analysis, “ Science 245:1073-1080, 1989.

Langfelder, E. J., National Center for Human Genome

Research, National Institutes of Health, personal

communication, November 1991.

Izbo, R. V., Cunningham, G., Simons, M. J., et al.,

“Defining DNA Diagnostic Tests Appropriate for

Standard of Clinical Care,” American Journal of

Human Genetics 47:583-590, 1990.

Lxxnna, W. K., Feldman, G. L., Kerem, B.-S., et al.,

‘‘Mutation Analysis for Heterozygote Detection and

the Prenatal Diagnosis of Cystic Fibrosis,” New

England Journal of Medicine 322:291-296, 1990.

Lippman, A., ‘‘Prenatal Genetic Testing and Screening: Constructing Needs and Reinforcing Inequities, ’ American Journal of Law and Medicine

17:15-50, 1991.

Lippman, A., “Mother Matters: A Fresh Look at

Prenatal Diagnosis and the New Genetic Technologies, ” Reproductive Genetic Testing: Impact on

Women, proceedings of a conference, Nov. 21, 1991.

MacLusky, I., McLaughlin, F. J., and Levinson, H. R.,

“Cystic Fibrosis: Part l,” Current Problems in

Pediatrics, J.D. Lockhart (cd.) (Chicago, IL: Year

Book Medical Publishers, 1985).

Meaney, F. J., “CORN Report on Funding of State

Genetic Services Programs in the United States,

1990, ” contract document prepared for the U.S.

Congress, Office of Technology Assessment, April

1992.

Murray, T. H., “Ethical Issues in Human Genome

Research,” FASEB Journal 5:55-60, 1991.

National Center for Human Genome Research, National Institutes of Health, “NXH Collaboration

Launches Research on Education and Counseling

Related to Genetic Tests, ” Human Genome project

Progress, Oct. 8, 1991.

National Institutes of Health, Workshop on Population Screening for the Cystic Fibrosis Gene, ‘‘Statement From the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis

Gene, ” N~, England JOur~l Of Medicine 323:70-

71, 1990.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64,

65,

66.

67,

68.

69.

National Research Council, Committee for the Study

of Inborn Errors of Metabolism, Genetic Screening:

Programs, Principles, and Research (Washington,

DC: National Academy of Sciences, 1975).

National Research Council, Committee on Mapping

and Sequencing the Human Genome, A-Zapping and

Sequencing the Human Genome (Washington, DC:

National Academy Press, 1988).

Nelkin, D., and Tancredi, L., Dangerous Diagnostics: The Social Power of Biological Information

(New York, NY: Basic Books, 1989).

Ng, I. S, L., Pace, R., Richard, M. V., et al., “Methods

for Analysis of Multiple Cystic Fibrosis Mutations, ’

Human Genetics 87:613-617, 1991.

Pat-met, W. E., “AIDS and Quarantine: The Revival

of an Archaic Doctrine, Hofstra Law Review

14:137-162, 1985.

Parmet, W. E., “Legal Rights and Communicable

Disease: AIDS, the Police Power, and Individual

Liberty,” .Iournal of Health Politics, Policy, and

bW14:741-771, 1989.

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Screening and counseling for Genetic Conditions: The Ethical, Social, and Legal

Implications of Genetic Screening, Counseling, and

Education Programs (Washington, DC: U.S. Government Printing Office, 1983).

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Summing Up: The Ethical and Legal

Problems in Medicine and Biomedical and Behavioral Research (Washington, DC: U.S. Government

Printing Office, 1983).

Reilly, P., Genetics, Law, and Social Policy (Cambridge, MA: Harvard University Press, 1977).

Reilly, P., “Government Support of Genetic Services,” Social Biology 25:23-32, 1978.

Reilly, P., “Advantages of Genetic Testing Outweigh Arguments Against Widespread Screening, ’

The Scientist, Jan. 21, 1991.

Riordan, J. R., Rommens, J. M., Kerem, B.-S., et al.,

“Identification of the Cystic Fibrosis Gene: Cloning

and Characterization of Complementary DNA, ”

Science 245:1066-1072, 1989.

Roberts, L., “Cystic Fibrosis Pilot Projects Go

Begging, “ Science 250:1076-1077, 1990.

Rommens, J. M., Iannuzzi, M. C., Kerem, B.-S., et al.,

‘‘Identification of the Cystic Fibrosis Gene: Chromosome Walking and Jumping, ’ Science 245: 1059-

1065, 1989.

Rosenkrantz, B., Public Health and the State: Changing Views in Massachusetts, 1842-1936 (Cambridge,

MA: Harvard University Press, 1972).
66 ● Qstic Fibrosis and DNA Tests: Implications of carrier Screening

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80,

81.

82.

Schulrnan, J. D., Maddalena, A., Black, S. H., et al.,

“Screening for Cystic Fibrosis Carriers,’ American

Journal of Human Genetics 47:740, 1990.

Shoshani, T., Augarten, A., Gazit, E., et al., “Association of a Nonsense Mutation (W1282X), the Most

Common Mutation in Ashkenazi Jewish Cystic

Fibrosis Patients in Israel, With Presentation of

Severe Disease,’ American Journal of Human Genetics 50:222-228, 1992.

Singer, E., ‘‘Public Attitudes Towards Genetic Testing,’ Population Research andPolicyReview 10:235-

255, 1991.

Starr, P., The Social Transformation of American

Medicine (New York, NY: Basic Books, 1982).

U.S. Congress, Office of Technology Assessment,

The Role of Genetic Testing in the Prevention of

Occupational Disease, OTA-BA-194 (Washington,

DC: U.S. Government Printing Office, April 1983).

U.S. Congress, Office of Technology Assessment,

Human Gene Therapy, OTA-BP-BA-32 (Washington, DC: U.S. Government Printing Office, December 1984).

U.S. Congress, Office of Technology Assessment,

Technologies for Detecting Heritable Mutations in

Human Beings, OTA-H-298 (Washington, DC: U.S.

Government Printing Office, September 1986).

U.S. Congress, Office of Technology Assessment,

New Developments in Biotechnology: Public Perceptions of Biotechnology, OTA-BP-BA-45 (Washington, DC: U.S. Government Printing Office, May

1987).

U.S. Congress, Office of Technology Assessment,

Healthy Children: Investing in the Future, OTA-H345 (Washington, DC: U.S. Government Printing

Office, February 1988).

U.S. Congress, Office of Technology Assessment,

New Developments in Biotechnology: The Commercial Development of Tests for Human Genetic

Disorders, staff paper, February 1988.

U.S. Congress, Office of Technology Assessment,

Mapping Our Genes—The Genome Projects: How

Big, How Fast?, OTA-BA-373 (Washington, DC:

U.S. Government Printing Office, April 1988).

U.S. Congress, Office of Technology Assessment,

Infertility: Medical and Social Choices, OTA-BA358 (Washington, DC: U.S. Government Printing

Office, May 1988).

U.S. Congress, Office of Technology Assessment,

Artificial Insemination: Practice in the United

States: Summary of a 1987 Survey, OTA-BP-BA-48

(Washington, DC: U.S. Government Printing Office,

August 1988).

83.

84.

85.

86.

87,

88.

89.

90.

91.

92.

93.

U.S. Congress, Office of Technology Assessment,

Genetic Witness: Forensic Uses of DNA Tests,

OTA-BA-438 (Washington, DC: U.S. Government

Printing Office, July 1990).

U.S. Congress, Office of Technology Assessment,

Genetic Monitoring and Screening in the Workplace,

OTA-BA-455 (Washington, DC: U.S. Government

Printing Office, October 1990),

U.S. Congress, Office of Technology Assessment,

Medical Monitoring and Screening in the Workplac+

Results of a Survey, OTA-BP-BA-67 (Washington,

DC: U.S. Government Printing Office, October

1991).

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and DNA Tests: Policies, Practices,

and Attitudes of Genetic Counselors-Results of a

Survey, OTA-BP-BA-97 (Washington, DC: U.S.

Government Printing Office, forthcoming 1992).

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and DNA Tests: Policies, Practices,

and Attitudes of Health Insurers-Results of a

Survey, OTA-BP-BA-98 (Washington, DC: U.S.

Government Printing Office, forthcoming 1992).

U.S. Department of Health and Human Services,

Healthy People 2000: National Health Promotion

and Disease Prevention Objectives, Conference Edition (Washington, DC: U.S. Government Printing

Office, 1990).

U.S. Department of Health and Human Services,

Health Services Administration, Genetic Services

Branch, State Luws and Regulations on Genetic

Disorders (Washington, DC: U.S. Department of

Health and Human Semices, 1980).

U.S. Department of Health and Human Services,

National Institutes of Health, National Center for

Human Genome Research, RFA #HG-91-01, NIH

Guide to Grants and Contracts 20(14), Apr. 5,1991.

Wertz, D. C., and Fletcher, J. C,, “An International

Survey of Attitudes of Medical Geneticists Toward

Mass Screening and Access to Results,” PubZic

Health Reports 104:3544, 1989.

Wertz, D. C., Rosenfield, J. M., Janes, S. R., et al.,

“Attitudes Toward Abortion Among Parents of

Children With Cystic Fibrosis,” American Journal

of Public Health 81:992-996, 1991.

Wilfond, B. S., and Fost, N., “The Cystic Fibrosis

Gene: Medical and Social Implications for Heterozygote Detection,” Journal of the American Medical

Association 263:2777-2783, 1990.
Chapter 3

Medical Aspects
Contents

Page

PATHOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Gastrointestinal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Reproductive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sweat Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Skeletal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DIAGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sweat Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Immunoreactive Trypsin Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .

DNA Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

TREATMENT AND PROGNOSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chest Physical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lung Transplants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Psychological Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUS1ONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .

69

69

70

71

71

72

72

72

72

73

73

73

76

77

77

78

79

79

Box

3-A. Cystic Fibrosis Therapies on the Horizon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Figures

3-l. Organ Systems Affected in Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

3-2. Distribution of Cystic Fibrosis Centers in the United States . . . . . . . . . . . . . . . . . . . . . . 74

3-3. Median Survival of U.S. Cystic Fibrosis Patients Over Time . . . . . . . . . . . . . . . . . . . . . 77

3-4. Age Distribution of U.S. Cystic Fibrosis Patients in 1990 . . . . . . . . . . . . . . . . . . . . . . . . 78

Tables

3-l. Sweat Chloride Levels in Normal and Cystic Fibrosis-Affected Individuals . . . . . . . 72

3-2. Medications Used in Management of Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Chapter 3

Medical Aspects

For a 17th century mother, tasting salt on her

baby’s brow portended death; according to folk

wisdom of the period, the infant was hexed. Modern

medicine now recognizes this as an indicator of

cystic fibrosis (CF), the most common, lifeshortening, recessive genetic disorder among Caucasians. CF also occurs in other races, but at a 4- to

36-fold lower incidence. A multifaceted condition,

CF compromises many functions throughout the

body, but varies from patient to patient in severity of

symptoms and the extent to which different organs

are affected. No cure exists for CF, but treatment of

the digestive and respiratory symptoms lengthens

lifespan considerably.

While the devastating consequences of CF have

been apparent for centuries, an understanding of its

underlying mechanisms is relatively new. Since the

1940s, doctors and scientists have known that CF is

a heritable condition—i.e,, one transmitted from

parents to children through their genes. New scientific developments have revealed the nature of the

genetic defect and offer insight into the relationship

between genetics and disordered function, clearing

the way to increased comprehension of the manifestations of CF and better management of the condition. Today, new therapeutic possibilities for affected patients exist, as well as technologies to

detect people who are asymptomatic carriers of CF

mutations.

This chapter provides an overview of the medical

principles important to understanding the context of

carrier screening for CF. It describes CF’s manifestations, outlines how the condition is diagnosed, and

summarizes methods of treatment. Additionally, this

chapter looks forward, considering new medical

techniques that could improve therapy and prognosis for people with CF.

PATHOLOGY

CF affects the respiratory, gastrointestinal (GI),

and reproductive systems, as well as the sweat

glands. Although the disorder is present at birth in

affected persons, the symptoms vary among individuals. Approximately 10 percent of people with CF

are born with a detectable intestinal blockage called

meconium ileus. In general, diagnosis occurs by age

3, although some individuals do not develop symptoms until later in childhood, adolescence, or even

adulthood (10,15,54,62).

CF generally involves dysfunction of exocrine

glands, the glands that secrete into ducts or onto

specific organ surfaces. Exocrine glands include

lacrimal (tear) glands, sweat glands, and part of the

pancreas. Mucus-producing cells lining the respiratory and GI tracts are also part of the exocrine

system. Although specific glands are impaired to

differing degrees, CF affects both major classes of

exocrine glands-the serous and mucous types. In

CF, secretions from serous glands have an increased

salt content. In contrast, secretions from mucous

glands have a normal or diminished salt content, but

the disorder causes them to be thicker than normal

secretions, leading to obstruction of the gland’s

ducts (49).

Respiratory System

CF affects both the lower respiratory tract (the

lungs) and the upper respiratory tract (the nose and

sinuses), although the upper tract is less involved

(figure 3-l). CF produces thick, sticky mucus that

obstructs breathing passages and interferes with

normal gas exchange and removal of bacteria,

viruses, and other particles from the airways. Thus,

individuals with CF often suffer chronic lung

infections, followed by inflammation, then subsequent lung damage (8,24,30,54). What often begins

as coughing and wheezing can progress over time to

shortness of breath, limited lung function, chronic

lung infections, and numerous pulmonary complications that often include respiratory and heart failure.

Three types of bacteria, Staphylococcus aureus,

Haemophilus influenzae, and Pseudomonas aeruginosa, generally colonize the lungs of CF patients.

The former two are usually the frost bacteria found

in CF-affected bronchi, while Pseudomonas more

frequently occurs as the disease progresses. Pseudomonas infection poses additional problems because

it is often resistant to antibiotics.

The severity of respiratory problems often determines the quality of life and survival of CF patients

(15,37,54). At one extreme, some infants develop

chronic lung obstruction and infection soon after

-69-
70 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Upper

respiratory

tract

Lower

respiratory

tract

Gastrointestinal

system

Figure 3-l-Organ Systems Affected in Cystic Fibrosis

I

I

I

system

SOURCE: Office of Technology Assessment, 1992.

birth, resulting in impaired pulmonary function and The pancreas, liver, gallbladder, stomach, and intesearly death. Other patients experience only mild tines can be affected, but if treated properly the

symptoms, living several decades before they suc- problems generally are not life-threatening (figure

cumb to progressive lung disease and heart failure. 3-l).

Gastrointestinal System About 85 to 90 percent of individuals with CF

experience some pancreatic problems, primarily

Digestive difficulties are common in CF and often because inadequate quantities of pancreatic enpredominate over respiratory symptoms early in life. zymes are released to digest food (22,54). As in the
Chapter 3-Medical Aspects ● 71

lugs, overly thick secretions are produced by the

exocrine pancreatic ducts. Digestive enzymes are

trapped, leading to destruction of pancreatic tissue

and preventing the enzymes from reaching the

intestines, where they are needed for digestion. Poor

nutrition and impaired growth result because food—

particularly fat and protein-is not broken down

appropriately and cannot be absorbed by the body.

Nutritional status and pulmonary disease appear

related; adequate nutrition helps alleviate the symptoms of pulmonary disease, whereas poor nutrition

reinforces pulmonary disease and worsens the prognosis (37,54). The inability to digest fat interferes

with intestinal absorption of fat-soluble vitamins—

A, D, E, and K. Vitamin deficiencies lead to

complications such as impaired blood clotting and

scaly skin. Resticted protein digestion also causes

serious problems, including edema in infants due to

lack of blood proteins. Insufficient release of pancreatic enzymes can cause large, greasy, malodorous

stools, abdominal pain or discomfort, and excessive

gas.

Pancreatic manifestations also include diabetes

and pancreatitis, although both are less frequent

complications than exocrine pancreatic insufficiency.

Diabetes, rare in CF patients under age 10, occurs in

10 percent of patients between ages 10 and 20, and

is found in an additional 10 percent with each decade

thereafter. CF-associated diabetes is mild compared

to juvenile-onset diabetes; it tends not to cause the

severe manifestations seen with the latter disease,

such as nerve lesions and skin ulcers. Pancreatitis,

inflammation of the pancreas, occurs in 1 percent of

CF patients (54).

In the GI tract and associated organs, thick mucus

accounts for many of CF’s clinical signs. As

mentioned earlier, meconium ileus occurs in 10

percent of newborns with CF. In these babies,

meconium (fetal stool) obstructs part of the small

intestine, the distal ileum. Older CF patients can

develop a condition akin to meconium ileus--distal

intestinal obstruction syndrome-where intestinal

contents either partially or completely block the

intestine (10,54,62).

CF patients suffer, less frequently, two additional

GI complications: intussusception, or the folding of

a piece of the intestine within itself, and rectal

prolapse, or projection of the rectum through the

anus (10,54). Finally, the liver is generally unaffected, although biliary cirrhosis<caused by blockage of the ducts that transport bile into the intestine—

and fatty liver can occur, generally late in the course

of the disease (10,54). In 1990, liver complications

caused death in approximately 4 percent of people

with CF (27).

Reproductive System

CF manifests itself in the reproductive systems of

males and females (figure 3-l); for both, sexual

development can be delayed. CF damages the

Wolffian duct, the embryological precursor of the

male reproductive organs, in 95 percent of CFaffected males (10). The vas deferens is often absent

(57), incompletely formed, or blocked by mucus,

resulting in an effect similar to vasectomy. Additionally, sperm might be improperly formed in men with

CF (39,65). As a result of these factors, only 2 to 3

percent of CF males are fertile (10). DNA analysis

of men with congenital absence of the vas deferens

reveals that many with this disorder might have CF,

although they have no apparent symptoms of CF

other than infertility (5).

In women with CF, thick, dehydrated mucus

centaining abnormal electrolytes often plugs the

opening to the uterus, impeding sperm migration and

reducing the pregnancy rate. Additionally, women

patients can develop amenorrhea secondary to pulmonary disease and poor nutritional status, further

reducing the chances of conception. Fertility in

women with CF is estimated at 2 to 20 percent; this

figure, however, might bean underestimate as many

women with CF use contraceptives ( 10, 15,27,42,54).

In patients with advanced lung disease, the physical

strain of pregnancy poses a health risk. Nevertheless, with proper care, increasing numbers of women

with CF are successfully having children. Women

with milder symptoms tolerate pregnancy better

than those with advanced lung disease.

Sweat Glands

CF also manifests in the sweat glands of affected

individuals (figure 3-l). Patients lose excessive

amounts of salt in their sweat, predisposing them to

episodes of salt depletion. Although not a major

concern for children and young adults—who can

take salt tablets to compensate-infants can suffer

form potentially fatal salt loss, particularly during

periods of warm weather (10,54,62).
72 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Skeletal System

Skeletal system problems occur in some CF

patients, probably secondary to the pulmonary and

digestive malfunctions. Many-but not all—

children with CF are short in stature and also have a

delayed growth spurt. Other skeletal affects include

joint pain, spine curvature (kyphosis), and clubbing

(swelling) of fingers and toes (10,54,62).

DIAGNOSIS

Physicians combine clinical criteria and laboratory tests to diagnose CF. Early signs and symptoms

can include recurrent wheezing, persistent cough

and excessive mucus, recurrent pneumonia, intestinal obstruction, low weight gain despite normal

eating (failure to thrive), abnormal bowel movements, rectal prolapse, salty taste to the skin, nasal

polyps, and enlargement of the fingertips. Since

many childhood ailments share symptoms with CF

and since its symptoms vary in severity from

individual to individual, CF is often undiagnosed or

misdiagnosed (10,15). Physicians identify some

newborns before they develop symptoms through

assays performed because of a family history of CF.

Family history of CF also contributes to diagnosis

for older individuals.

Sweat Test

The sweat test is the most common method for

confirmin g CF. CF affects exocrine glands, including sweat glands. In these glands, excess sodium

(Na+

) and chloride (Cl-) ions are lost to the sweat.

This indicator was frost discovered in 1953; by 1959,

it was being used to diagnose CF (29).

To measure the salt content in the sweat of an

individual, sweating is induced by placing apilocarpinesoaked gauze pad or falter paper on the person’s arm

or back. (Pilocarpine activates sweat glands.) A low

electric current is passed through the area (iontophoresis) for 4 to 6 minutes to drive the pilocarpine

into the sweat glands. Next, the skin is cleaned and

a sterile, preweighed, dry gauze pad is taped to it.

Sweat is collected for up to an hour to obtain an

adequate amount (100 mg), then the pad is weighed

and sweat volume deterrnined. Finally, the sweat is

rinsed out of the pad and the pad weighed to

ascertain salt content. Elevated Cl- levels confirm a

diagnosis of CF (17) (table 3-l). The testis generally

repeated in positive cases, as well as in borderline or

negative cases where symptoms still strongly sugTable 3-l--Sweat Chloride Levels in Normal and

Cystic Fibrosis-Affected Individuals

Sweat chloride

(mmol/L) Status

<40 Normal

40 to 60 Borderline

>60 Presumptive case of CF

SOURCE: Office of Technology Assessment, 1992.

gest CF. Some laboratories measure both Na+ and

Cl- content in sweat.

Although painless and of moderate expense, the

sweat test has several drawbacks. As with all

diagnostic tests, accuracy depends on how the testis

performed and interpreted. Pilocarpine iontophoresis

is difficult to perform on newborns under 8 weeks of

age, making sweat testing in newborns difficult.

Moreover, complications of CF—such as edema

(swelling)---or recent use of corticosteroids can

confound the results. Other conditions also yield

elevated Cl- levels in perspiration, although these

can generally be distinguished from CF by their

symptoms. Additionally, normal adults, in rare

instances, have increased levels of Cl- in their sweat.

One study found approximately 40 percent of

persons referred to CF centers were sent there as a

result of false sweat test results by the initial tester

(10). Though the sweat test is imperfect, when

performed properly and considered in conjunction

with typical clinical findings, it can be used to

diagnose CF with better than 98 percent accuracy

(9). Increasingly, DNA analysis is used to establish

a positive CF diagnosis in people with borderline

sweat test results (68).

Immunoreactive Trypsin Test

A protocol for newborn CF screening, the immunoreactive trypsin (IRT) test, measures levels of

pancreatic trypsin, a digestive enzyme (13,54). In

newborns with CF, obstruction of the exocrine

pancreatic ducts causes this enzyme to backup into

the circulatory system. In the IRT test, a drop of

blood is isolated on a card, dried, and chemically

analyzed to detect elevated levels of the enzyme

(71). This use of dried spots—known as “Guthrie

spots’ ‘—parallels the method of newborn screening

for a range of genetic disorders (e.g., phenylketonuria and hypothyroidism) performed by a number of

States (4).

While sweat testing is intended to be diagnostic,

the IRT test is not. The IRT test yields a higher
Chapter 3-Medical Aspects ● 73

number of false positives (unaffected individuals

incorrectly suggested to have CF) and false negatives (affected individuals incorrectly identified as

not having CF) than the sweat test (7,55). For this

reason, it requires followup with other procedures

for conclusive diagnosis,

Current pilot studies combine the use of the IRT

test with other tests to enhance its diagnostic value.

In a Colorado study, the false positive rate of IRT

alone was reduced by sequential use of the IRT test

with a stricter threshold and the sweat test (34,36).

Programs in Wisconsin, Pennsylvania, and Australia

combine the IRT test with followup DNA analysis

for a single mutation, known as DF508 (53,56,70).

The efficacy of presymptomatic identification of the

disease in newborns remains uncertain (1,36).

DNA Analysis

Both sweat testing and IRT analysis measure

phenomena secondary to the genetic cause of CF. In

contrast, DNA analysis directly examines the genetic material, DNA, to reveal whether an individual

has CF mutations. Currently, DNA analysis is used

for prenatal detection, carrier screening, and, increasingly, determining the status of borderline cases

(3,68). DNA analysis has also been used in combination with the IRT test for newborn screening (56,70).

As detailed in chapter 4, more than 170 different

mutations cause CF, complicating prospects for

routine diagnosis using DNA assays. While direct

analysis of DNA is theoretically the most precise

diagnostic test, at present it can only be used to

diagnose positive cases. Due to the number of

different mutations—many of which are not included in test panels-DNA analysis cannot confirm

that a person does not have CF. However, DNAbased CF mutation tests, while not yet ready for sole

use as a diagnostic test in negative cases, are

accepted as conclusive in positive cases. In its 1991

patient registry, the Cystic Fibrosis Foundation

(CFF) accepted positive results from DNA tests

without requiring sweat test confirmation (68).

(Chapter 4 discusses the correlation of molecular

diagnosis with clinical outcome.)

TREATMENT AND PROGNOSIS

The goal of CF treatment is to maintain a stable

condition for long periods of time and allow affected

individuals to lead relatively normal lives. General

therapy involves home treatment, with occasional

hospital stays as needed. The regularity of hospitalization varies with the individual, and ranges from

infrequent to once every 2 to 3 months, often

increasing in frequency in the last few years of life.

Treatment seeks to control infection, promote mucus

clearance, and improve nutrition.

The daily therapeutic regimen for a person with

CF depends on the severity of the disease, but the

principal components of treatment focus on managing the pulmonary and digestive manifestations of

CF. Even in asymptomatic cases, regular visits to a

physician are generally advised to prevent problems

and to detect early problems when complications do

arise. Today, treating CF has become increasingly

specialized. Currently, more than 110 major clinical

centers and a number of satellite centers and

outreach clinics are devoted to delivering CF care

(16,17) (figure 3-2). The CFF, founded in 1955, has

played a large role in advancing CF treatment and

care.

Medical Management

Medical management of CF focuses on:

●

●

●

●

alleviating blockage in the airways,

fighting lung infection,

managing airways inflammation, and

facilitating proper nutrition.

Lung Therapy

Lung therapy for CF requires both medical and

physical approaches. Medical management of lungrelated problems involves the use of aerosols,

bronchodilators, corticosteroids, and antibiotics (table

3-2). Aerosols deliver medications and water to the

lower respiratory tract; most use a saline solution as

the vehicle. Mucolytics, agents (generally N-acetyl

cysteine) designed to break up mucus, can be used

in aerosol form, Efficacy and safety of currently

available mucolytics are controversial, but new

mucolytics under development might prove safer

and more appropriate for routine use. Bronchodilators are also used to reverse airway obstruction.

These drugs are delivered by aerosol, injection, or

orally. Bronchodilators used to treat CF include

metaproterenol, isoetharine, and albuterol. In some

instances, physicians prescribe corticosteroids to

treat allergic reaction to a fungus that grows in CF

airways. Long-term corticosteroid therapy is not

generally beneficial (9). Finally, nonsteroidal antiinflammatory medications for CF therapy are cur-
74 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 3-2—Distribution of Cystic Fibrosis Centers in the United States

/ “-T----

● %

o

0 }

v

SOURCE: Office of Technology Assessment, 1992.

rently being evaluated. Most of these treatments

involve some degree of controversy as to efficacy

and long-term safety (11,25,64).

As with all therapies, each of these treatments is

useful in some patients and not in others. In some

patients, for example, currently available mucolytic

aerosols induce cough, cause bronchospasm, and

promote inflammation; bronchodilators, while often

providing immediate relief of symptoms, might not

be effective in long-term use and could even prove

harmfud. Short-term use of corticosteroids in adults

can cause detrimental effects such as immune

system suppression, hyperglycemia, and glycosuriarequiring their use be evaluated on a patient-bypatient basis (25).

In contrast to the use of aerosols, bronchodilators,

and corticosteroids (which ameliorate the physiological effects of CF on the lung), antibiotic treatment reduces or eliminates infection, thus slowing

● Cystic fibrosis center

o Satellite center

❑ Outreach clinic or center

inflammatory responses that can lead to progressive

lung disease. Unlike other therapies, antibiotic

treatment is not controversial. The major antibiotics

for countering CF-related infections include the

penicillins and the aminoglycosides (e.g., gentamicin). Quinolones (e.g., ciprofloxacin and norfloxacin),

cephalosporins, and other antibiotic families are also

used. Antibiotics can also be aerosolized.

Treatment with antibiotics varies from intermittent use to repeated, sustained use. CF patients often

need much larger doses than persons without CF. As

with all long-term antibiotic treatment, bacterial

resistance to treatment is a major problem. While

antibiotic therapy is generally provided on an

outpatient basis, hospitalization is sometimes necessary. Lengths of stay vary, but can range as long as

2 to 3 weeks. Hospitalization allows more careful

management of patients, as well as the use of

antibiotics that must be given intravenously. The
Chapter 3---Medical Aspects . 75

Table 3-2—Medications Used in Management of Cystic Fibrosis

Type of medication Purpose

Fight bacteria in lungs

Streptococcus

Haemophilus

Pseudomonas

Pseudomonas

Staphylococcus

Haemophilus

Pseudomonas

Pseudomonas

Pseudomonas

Open air passages, facilitate breathing

Dissolve mucus

Digest food

Maintain nutrition

Stimulate kidneys to remove water; relieve fluid

accumulation throughout body; ease pumping burden on heart

SOURCE: Office of Technology Assessment, 1992, based on D.M. Orenstein, Cystic Fibrosis:A Guide for Patient and

Family(New York NY: Raven Press, Ltd., 1989).

necessity of hospitalization, however, remains controversial. Recent evidence indicates that less expensive home intravenous treatment could be as effective as identical hospital-based treatment if the

patient complies. Although antibiotics are standard

treatment, the method of delivery, selection of

particular antibiotics, and the usefulness of prophylactic treatment are debated. Finally, in addition to

aerosols, bronchodilators, corticosteroids, and antibiotics, several new methods to manage CF are

foreseeable (box 3-A).

Digestive Therapy

Digestive therapy for CF has several goals—

achieving ideal weight, insuring normal growth and

maturation, sustaining respiratory muscle strength,

and maintaining adequate immunity. The major

components of digestive therapy are pancreatic

enzyme replacement, administration of fat-soluble

vitamins, and dietary supplementation.

For pancreatic enzyme replacement therapy, extracts of animal pancreas are ingested orally. Replacing pancreatic enzymes enables CF patients to

properly digest food and absorb nutrients. Enzymes

must be taken each time a person eats. Dietary

supplementation is important to compensate for

increased energy needs associated with CF. Many

people with CF need approximately 150 percent of

normal caloric intake. Recommended supplements

are high-calorie, consisting of high-protein foods,

medium-chain triglycerides, and simple carbohydrates. In severe cases of malnutrition or during

acute periods of lung infection, nasogastric feeding

or total parenteral nutrition can be necessary.
76 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 3-A-Cystic Fibrosis Therapies on the Horizon

Standard CF pulmonary treatments of the past few decades focused on fighting infection and clearing mucus

in the airways, but new therapies target preventing the process of infection and subsequent inflammatory response

(12,19). These therapies attempt to intervene at specific junctures in the disease process by:

. decreasing the viscosity of lung secretions;

. protecting the airway from destruction and preventing infection;

● correcting the ionic imbalance; and

. compensating for the genetic defect through gene therapy.

Two promising drugs-DNase and amiloride-thin CF lung secretions through different mechanisms. Both

are in clinical trials for approval by the U.S. Food and Drug Administration (FDA) (42,58). DNase is an enzyme

that breaks down DNA that accumulates from the debris of inflammation-fighting cells in the lungs of CF patients.

DNase loosens CF mucus in vitro and in vivo, and is safe for short-term use (2,38,60,61); long-term studies are

underway (58). In short-term studies, patients using DNase show noticeable improvement in breathing ability,

suggesting that it might be an effective CF therapy in the near future (40). Company officials anticipate that DNase

might be on the market in early 1993 (6). Amiloride is a diuretic that loosens lung secretions by blocking sodium

ion reabsorption (43). Clinical trials demonstrating safety and efficacy of its use in aerosol form are in progress (42).

The FDA has announced plans to streamline its drug approval process, a decision that could make treatments such

as DNase and amiloride commercially available soon (69).

Ironically, the body’s natural infection fighting mechanism contributes to the massive destruction of airways

in CF patients. Substances known as antiproteases can protect the airway epitheliums from injury caused by innate

bacterial defense substances. Included in this category are alpha-l-antitrypsin, secretory leukocyte protease

inhibitor, and a compound known as ICI 200,880, all undergoing clinical trials for FDA approval (8,42,51).

Other potential therapies circumvent the environment that leads to infection and subsequent buildup of cells.

These new therapies attempt to correct the ion imbalance characteristic of CF (ch. 4). Admini “ stration of adenosine

triphosphate and uridine triphosphate in conjunction with the diuretic arniloride stimulates chloride ion (Cl-)

secretion, and could mitigate the effects of decreased Cl- conductance in individuals with CF; FDA clinical studies

are in progress (42,44). Recent in vitro evidence that proper chloride conductance can be induced in some CF cells

by applying large doses of cyclic-AMP-stimulating drugs suggests this as a future avenue for pharmaceutical

intervention (18,20,73).

Unlike treatments that attack symptoms of CF, gene therapy is designed to rectify the deficits of the disease

by directly altering DNA. In theory, new DNA can be inserted into faulty cells to compensate for the genetic defect.

Gene therapy for CF (discussed in greater detail in ch. 4) is in the animal experiment stage at present. Using a

crippled virus specific to airway epithelial cells, the normal human CF gene was administered directly to the lungs

of rats by aerosol spray. After 6 weeks, the transferred DNA continued to function (14,59). Aerosolized liposomes,

fatty capsules that can transport drugs directly into cells, have been used to deliver alpha-1 -antitrypsin genes into

rabbit lungs, and a similar mechanism might be used to deliver the CF gene to the lungs (35). Despite significant

experimental progress, however, many hurdles remain for CF gene therapy to be feasible in humans. Long-term

safety of the procedure needs to be demonstrated and questions need to be answered regarding the most appropriate

means of transfeming the gene, the number of cells that need to be corrected, and the duration of treatment.

SOURCE: Oftice of Technology Assessment, 1992.

Chest Physical Therapy assistant (e.g., a professional therapist or a family

member) claps on the chest or back to loosen mucus

The cornerstone of CF treatment is chest physical while the patient coughs it up. Mechanical percustherapy (PT) to move the mucus that blocks major air sors and vibrators can facilitate PT. People with CF

passages out of the lungs (10,15,54). Bronchial generally require PT one to four times daily,

drainage, also called postural drainage, is a specific depending on their clinical status. When flareups in

form of chest PT commonly used for CF, and CF symptoms or acute infection occur, the freinvolves turning the body in various positions to quency of chest PT generally increases. In light of

align air passages in the lung to optimize the effect the time commitment required to accomplish PT-at

of gravity. It is usually performed leaning on a table least once a day for 20 minutes or longer—

or lying over a couch. Either the individual or an compliance is often poor.
Chupter 3-Medical Aspects ● 77

Lung Transplants

Since the 1980s, two new options have become

available to treat the terminal stages of CF:

heart-lung and double-lung replacement surgery

(23,26,47,66). Through 1991, 140 heart-lung transplants have been performed in CF patients internationally, with 89 patients still alive (26,47). Since

1986, 58 double-lung transplants have been performed in CF patients; 40 patients were surviving in

1991 (26). As with all organ transplantation, rejection is the major obstacle to survival. Availability of

donor organs and cost are also limiting factors.

When lungs were available, the operation and

aftercare cost approximately $200,000 in 1989 (47).

Heart-lung transplant was pioneered first, and

appears better suited for CF patients with right heart

failure. Double-lung transplants are increasing in

frequency (66), and they appear to reduce the

incidence of acute and chronic infection. While the

sputum of CF patients after transplant can become

colonized with Pseudomonas bacteria, it generally

clears in the succeeding months (47,66). Since most

CF patients do not require new hearts, leaving the

original heart intact avoids coronary artery disease

associated with rejection of the transplant. It also

removes the CF patient from the competition for

donor hearts (31,47).

To be considered for transplant therapy, a patient

must be a nonsmoker who has no signs of other

systemic or pleural disease, does not take high doses

of steroids, is within 15 percent of ideal weight, and

has an emotionally supportive family (23,26,47,66).

Neither approach can cure CF: Both types of

transplants leave the pancreatic, GI, reproductive,

and sweat gland manifestations of CF unresolved.

Prognosis

Survival data for individuals with CF change

rapidly (figure 3-3), Fifty years ago, most infants

born with CF died within the frist 2 years of life. In

1959, the median age at death was 4 years. Median

age at death has increased one year per year for the

past decade (33). In 1990, the median age at death

had progressed to 28 years-meaning that one-half

of babies born with CF in 1963 were alive in 1990

(27,28). The CFF reports that estimating the life

expectancy of an infant born with CF today would

require data from considerably more years than have

been collected and is thus not feasible (52). Some

research indicates past improvements in survival

Figure 3-3-Median Survival of U.S. Cystic Fibrosis

Patients Over Time

Calendar year

SOURCE: Office of Technology Assessment, 1992, based on S.C. FitzSimmons, “Cystic Fibrosis Patient Registry, 1990: Annual Data

Report,” Cystic Fibrosis Foundation, Bethesda, MD, January

1992; and S.C. FitzSimmons, Cystic Fibrosis Foundation,

Bethesda, MD, personal communication, February 1992.

might not continue without further advances in

therapy: Data from Canada show a plateau in median

survival age at 28 years over the last decade (21).

Nevertheless, a few postulate median survival of an

infant born in 1992 with CF might be 40 years (12).

Three medical factors account for the increased

life expectancy of persons with CF: the advent of

antibiotics in the 1940s, the introduction of chest PT

in the 1950s, and advances in nutrition in the 1970s

and 1980s. Past failure to diagnose mild cases of CF

also probably negatively skewed median survival

data. And, the development of CF centers providing

specialized and comprehensive care likely has

contributed to longevity. Currently, people with CF

can often lead full lives for long periods and can

pursue college educations, maintain careers, marry,

and have families.

As noted earlier, CF follows a varied clinical

course. A few affected babies die from meconium

ileus within the first days of life, while some people

can be largely asymptomatic for 10 years (figure

3-4). Certain prognostic factors help predict survival. Lung function measured by a clinical test

helps predict short-term survival, particularly when

considered with respect to age and gender (41).

Mortality rates in children and adolescents are

higher than in adults with similar measured lung

function (41). Likewise, mortality rates are higher in

females than males with comparable lung function

(41). In general, males live a few years longer than
78 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 3-4-Age Distribution of U.S. Cystic Fibrosis —

o-5

6-10

11-15

_ 16-20

~ 21-25

~ 26-30

~ 31-35

36-40

41-45

46-50

51-55

—

Patients in 1990 -

1

I I I I

I o 1 2 3 4 5

Number of persons (thousands)

SOURCE: Office of Technology Assessment, 1992, based on S.C. FitzSimmons, “Cystic Fibrosis Patient Registry, 1990: Annual Data

Report,” Cystic Fibrosis Foundation, Bethesda, MD, January

1992.

females (27). Africa.n Americans have more difficulty during the early years of life, but fare better

than Caucasians later (10). Psychosocial aspects of

the disease also affect prognosis. Denial, dependence, and depression-on the part of either parent or

patient-result in poor compliance with therapeutic

regimens and poor prognosis. Other signs of poor

prognosis include respiratory complications before

age 1, abnormal chest x-ray at diagnosis, or inadequate nutritional status. Clinically mild symptoms at

the time of diagnosis and pancreatic sufficiency both

predict longer survival (10). Certain CF mutations

associate with severe lung disease, while others

cause milder forms (9,67,72).

The effect of early diagnosis on clinical outcome

is unclear, and whether neonatal screening for CF is

useful remains controversial. Some clinical experience supports the belief that earlier diagnosis, and

hence earlier treatment, improve prognosis. However, when and where patients are treated has a

significant effect on outcome (10). Long-term data

from neonatal screening programs in Colorado and

Wisconsin could settle this issue (1,34,36,70).

Psychological Aspects

Beyond physical ailments, people with CF and

their families experience emotional and social effects. As in any chronic illness, being sick adds

additional strain to life. In particular, because CF

requires daily treatments-even mildly affected

individuals require digestive enzymes and usually

chest PT---the disease affects the daily lives of the

affected person and his or her family. Psychological

response to the demands of the disease and outlook on life vary considerably (45,50,63). Not all

individuals with CF and their families experience

all-or even most—negative emotional aspects of

the disease; in particular, those with milder cases

grow up with little disruption to their lives. Specific

feelings and reactions, however, typify particular

periods in both the life of the individual and the

course of CF (15,54,62).

Children, adolescents, and adults with CF react

differently to the condition, Children sometimes

resist home care, such as chest PT, because it

intrudes on play time and interferes with their desire

for independence. Children can be sensitive to being

different from their peers, and can be embarrassed by

physical manifestations of the disease such as

flatulence, coughing, and dietary restrictions. Missing school due to frequent lung infections or

hospitalizations interferes with school work; hospitalization can be a stressful and frightening experience. Children above age 10 start worrying about the

seriousness of CF and the possibility of death,

feelings that are exacerbated when they see friends

succumb to the disease (48,62).

CF accentuates the fears, conflicts, and insecurities associated with adolescence. At a time when

they most want to be independent of their parents,

teenagers with CF frequently depend on them for

daily chest PT and other medical necessities. Some

teenagers refuse to take enzyme supplements or

medication to rebel against parental attempts to keep

them healthy. The short stature, delayed onset of

secondary sex characteristics, and sometimes impaired athletic ability characteristic of CF can be

traumatic for adolescents who feel acutely aware of

their bodies and seek peer approval. Nonetheless,

many teenagers with CF are as psychologically

healthy as their peers (15,50,54,62).

As the prognosis for CF improves, it increasingly

becomes a disease of young adulthood rather than a

disease of childhood (figure 3-4). Due to the

progressive nature of CF lung complications, many

adults are physically more restricted than they were

as children. If they go to college, young adults with

CF must factor the demands of daily chest PT, often

performed by family, into the decision of where to

attend. CF also influences career choice, since

individuals face frequent bouts of infection and can

be limited in physical activity. The need for health
Chapter Medical Aspects . 79

insurance also can shape job choice (ch. 8). The

threat of early death influences family planning

and marriage decisions as well. Within the medical community, a need exists for increased attention to CF care of adults, whose medical and psychological concerns differ from those of children

(17,46,48,54,63).

For the family of a child with CF, the disease often

shapes family time and interactions (54,62). With

the initial diagnosis, family members experience a

range of emotions: anger, shock, and grief that their

child has a life-threatening illness; denial of the

disease; relief to finally know definitely what is

wrong and what can be done (15,48,54,62). Having

a child with CF can cause conflicts in marriage and

social life. CF is time consuming, can limit family

vacations, and demands that parents have jobs that

provide adequate health insurance. For siblings, CF

can inspire resentment of the attention focused on

the sick child. When a sibling with CF dies, siblings

can feel guilt that they were responsible (15,48,54,62).

While the burden of CF can be emotionally

difficult, many individuals and their families persevere, leading full lives. The medical condition is

only part of the social context and environment that

creates the whole life. Since studies focus on the

negative impact of CF, it is much easier to enumerate

the difficult parts of the experience than it is to

document that many CF patients and families are

happy (15,62). For them, CF is just a part of life. As

one mother of a son with CF notes, no one—with or

without CF—is guaranteed a ‘ ‘perfect life or a

perfect child” (32).

SUMMARY AND CONCLUSIONS

CF is the most common, life-shortening, recessive

genetic disorder among Caucasians. Age of diagnosis and severity of symptoms vary greatly from

individual to individual. CF generally involves

exocrine gland dysfunction. It affects multiple organ

systems in the body, including the lungs, digestive

tract, reproductive organs, and sweat glands, as well

as the skeletal framework. The condition wreaks its

most severe toll, however, on the respiratory and

digestive systems, where it is characterized by

chronic obstruction and infection of the airways and

insufficiency of the pancreas in providing digestive

enzymes. Ultimately, the majority of people with CF

die from heart failure stemming from the respiratory

consequences of CF.

Diagnosis of CF usually follows from its clinical

symptoms, with confirmation by laboratory tests.

Currently, analysis of sweat is the simplest and most

reliable method for confirming CF. Measurement of

a pancreatic enzyme, trypsin, is used—imperfectly—to identify CF. DNA-based CF mutation tests

are not yet ready as the sole diagnostic test in

negative cases, but can be used to accurately

diagnose positive incidence.

Treating CF focuses on managing the respiratory

and digestive symptoms to maintain a stable condition, At present, lung obstruction is ameliorated by

daily chest PT and is sometimes augmented by

aerosols, bronchodilators, and corticosteroids. Antibiotics are used to fight infection. The drugs DNase

and amiloride, currently in clinical trials, offer hope

of attenuating obstruction as well, although they will

not be a substitute for chest PT To attain adequate

nutrition, pancreatic enzyme replacement and dietary supplementation are required. In a few endstage cases, double-lung or heart-lung replacement

alleviates CF-related pulmonary complications, although digestive difficulties remain and rejection of

the transplanted organs can limit longevity.

Research into the underlying basis responsible for

CF progresses at a rapid pace. In the coming decade,

new approaches to therapy, including amiloride and

nucleotide triphosphates, could decrease lung damage by combating primary manifestations at the

level of ion transport. Treatments that correct the

molecular deficit rather than ameliorating symptoms

seem feasible. Eventually, gene therapy to supplement the gene itself could be possible.

Over the past half-century, CF has evolved from

an illness nearly always fatal in childhood to one in

which numerous individuals now survive into adulthood. Currently, the median survival age is 28 years.

Advances in new therapies and comprehensive

approaches to patient care have all contributed to

longer lives for people with CF. The search for new

treatments, and ultimately a cure, might improve

future prognosis.

1

CHAPTER 3 REFERENCES

Abman, S, H., Ogle, J. W., Harbeck, R. J., et al., ‘Early

Bacteriologic, Immunologic and Clinical Courses of

Young Infants With Cystic Fibrosis Identified by

Neonatal Screening, ‘‘Journal of Pediatrics 119:21 1-

217, 1991.
80 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Aitken, M. L., Burke, W,, McDonald, G., et al.,

“Recombinant Human DNase Inhalation in Normal

Subjects and Patients With Cystic Fibrosis: A Phase

I Study, ’ Journal of the American Medical Association 267:1947-1951, 1992.

Amos, J., James, S., and Erbe, R., “DNA Analysis of

CF Genotypes in Relatives With Equivocal Sweat

Test Results,” Clinical and Investigative Medicine

13:1-5, 1990.

Andrews, L.B. (cd.), State L.uws and Regulations

Governing Newborn Screening (Chicago, IL: American Bar Foundation, 1985).

Anguiano, A., Oates, R. D., Amos, J. A., et al.,

“Congenital Bilateral Absence of the Vas Deferens:

A Primarily Genital Form of Cystic Fibrosis,”

Journal of the American Medical Association 267:

1794-1797, 1992.

Associated Press, “Therapy Found Effective for

Cystic Fibrosis,’ Washington Post, p. A3.

Beaudet, A. L., Howard Hughes Medical Institute,

Baylor College of Medicine, Houston, TX, personal

communication, September 1991.

Berger, M., “Inflammation in the Lung in Cystic

Fibrosis: A Vicious Cycle That Dws More Harm

Than Good?,” Clinical Reviews in Allergy 9:119-

142, 1991.

Boat, T. F., University of North Carolina at Chapel

Hill, Chapel Hill, NC, personal communication,

January 1992.

Boat, ‘llF., Welsh, M. J., and Beaudet, A. L., “Cystic

Fibrosis,’ The Metabolic Basis of Inherited Disease,

C.R. Scriver, A.L. Beaudet, W.S. Sly, et al. (eds.)

(New York, NY: McGraw Hill, 1989).

Burrows, B., and IAmwitz, M. D., “The ~-Agonist

Dilemma,” New England Journal of Medicine 326:

560-561, 1992.

Collins, F. S., “Cystic Fibrosis: Molecular Biology

and Therapeutic Implications, ’ Science 256:774-

779, 1992.

Crossley, J. R., Elliott, R. B., and Smith, P. A., “DriedBlood Spot Screening for Cystic Fibrosis in the

Newborn,” L.uncet 1:472, 1979.

Crystal, R. G,, National Heart, Lung, and Blood

Institute, National Institutes of Health, Bethesda,

MD, presentation before the U.S. Congress, Office of

Twhnology Assessment advisory panel on Cystic

Fibrosis and DNA Tests: Implications of Carrier

Screening, September 1991.

Cunningham, J. C., and Taussig, L. M., A Guide to

Cystic Fibrosis for Parents and Children (Bethesda,

MD: Cystic Fibrosis Foundation, 1989).

Cystic Fibrosis Foundation, Accredited Cystic Fibrosis Care Centers (Bethesda, MD: Cystic Fibrosis

Foundation, 1992).

Cystic Fibrosis Foundation, Center Committee and

Guidelines Subcommittee, “Cystic Fibrosis Founda18,

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

tion Guidelines for Patient Services, Evaluation, and

Monitoring in Cystic Fibrosis Centers,” Arizona

Journal of Diseases of Childhood 144:1311-1312,

1990.

Dalemans, W., Barbry, P., Champigny, G., et al.,

‘‘Altered Chloride Ion Channel Conductance Associated With AF508 Cystic Fibrosis Mutation, ’ Nature

354:526-528, 1991.

Davis, P. B., “Cystic Fibrosis From Bench to Bedside,” New England Journal of Medicine 325:575-

577, 1991.

Drumm, M.L., Wilkinson, D. J., Smit, L. S., et al.,

“Chloride Conductance Expressed by AF508 and

Other Mutant CFI’RS in Xenopus Oocytes,’ Science

254:1797-1799, 1991.

Durie, P. R., Department of Pediatrics, University of

Toronto, Toronto, Canada, personal communication,

June 1992.

Durie, P. R., and Forstner, G. G., ‘‘Pathophysiology of

the Exocrine Pancreas in Cystic Fibrosis,’ JournaZ of

the Royal Society of Medicine 82( Supp.):2-10, 1989.

Egan, TM., Westerman, J., Mill, M. R., et al., ‘‘Lung

Transplantation at UNC,” North Carolina Medical

Journal 52:325-329, 1991.

Elbom, J. S., and Shale, D.J., “Cystic Fibrosis. 2.

Lung Injury in Cystic Fibrosis,’ Thorax 45:970-973,

1990.

Fick, R. B., and Stillwell, P. C., “Controversies in the

Management of Pulmonary Disease Due to Cystic

Fibrosis,” Chest 95:1319-1327, 1989.

Fiel, S. B., “Mechanical Ventilation in the Severely

Ill Adult With Cystic Fibrosis,’ Pediatric Pulmonology 1991 North American Cystic Fibrosis Conference 6( Supp.):217-218, 1991.

FitzSimmons, S. C., “Cystic Fibrosis Patient Registry, 1990: Annual Data Report,” Cystic Fibrosis

Foundation, Bethesda, MD, January 1992.

FitzSimmons, S. C., Cystic Fibrosis Foundation, Bethesda, MD, personal communication, February 1992.

Gibson, L.E., and Cooke, R. E., “A Test for Concentration of Electrolytes in Sweat in Cystic Fibrosis of

the Pancreas Utilizing Pilocarpine by Iontophoresis,’

Pediatrics 23:545-549, 1959.

Gilligan, P. H., ‘‘Microbiology of Airway Disease in

Patients With Cystic Fibrosis,” Clinical Microbiology Reviews 4:35-51, 1991.

Goldsmith, M. F., “Which Transplant Technique

Will M Cystic Fibrosis Patients Breathe Easier?,”

Journal of the American Medical Association 264:9-

10, 1990.

Greenberg, G., Cystic Fibrosis Foundation, Metropolitan Washington, DC chapter, personal communication, December 1991.

Habbersett, C., Cystic Fibrosis Foundation, Bethesda, MD, personal communication, November

1991.
Chapter 3-Medical Aspects ● 81

34.

35.

36,

37.

38.

39.

40+

41.

42.

43.

44.

45.

46.

47,

48.

49.

Hammond, K. B., Abman, S. H., Sokol, R. J., et al.,

“Efficacy of Statewide Neonatal Screening for

Cystic Fibrosis by Assay of Trypsinogen Concentrations,’ New England Journal of Medicine 325:769-

774, 1991.

Holden, C. (cd.), “Aerosol Gene Therapy,” Science

253:964-965, 1991.

Holtzman, N. A., ‘‘What Drives Neonatal Screening

Programs?, ’ Ne~’ England Journal of Medicine

325:802-804, 1991.

Huang, N. N., Schidlow, D. V., Szatrowski, T. H., et

al., ‘‘Clinical Features, Survival Rate, and Prognostic

Factors in Young Adults With Cystic Fibrosis, ”

American Journal of Medicine 82:871-879, 1987.

Hubbard, R. C., McElvaney, N. G., Birrer, P., et al.,

“A Preliminary Study of Aerosolized Recombinant

Human Deoxyribonuclease in the Treatment of

Cystic Fibrosis, ’ New England Journal of Medicine

326:812-815, 1992,

“Infertility in Cystic Fibrosis, ’ Lancer 338:1008,

1991.

Jacoby, J. Z., III, Cystic Fibrosis Center, St. Vincent’s

Hospital and Medical Center, New York, NY,

personal communication, March 1992.

Kerem, E., Reisman, J., Corey, M., et al., ‘‘Prediction

of Mortality in Patients With Cystic Fibrosis, ’ New

England Journal of Medicine 326:1 187-1191, 1992.

Knowles, M. R., University of North Carolina at

Chapel Hill, Chapel Hill, NC, personal communication, February 1992.

Knowles, M. R., Church, N. L., Waltner, W. E., et al.,

“A Pilot Study of Aerosolized Amiloride for the

Treatment of Lung Disease in Cystic Fibrosis,’ New

England Journal of Medicine 322: 1189-1194, 1990.

Knowles, M, R., Clarke, L. L., and Boucher, R. C.,

“Activation by Extracellular Nucleotides of Chloride Secretion in the Airway Epithelia of Patients

With Cystic Fibrosis, ” Ne~’ England Journal of

Medicine 325:533-538, 1991.

Lavigne, J. V., ‘ ‘Psychological Functioning of Cystic

Fibrosis Patients, ” Textbook of Cystic Fibrosis, J.D.

Lloyd-Still (cd.) (Boston, MA: John Wright-PSG

Inc., 1983).

hwiston, N. J., “The CF ‘Young Adult’ Comes of

Age, ” Chest 97:1282-1283, 1990.

hwiston, N., Stames, V., and Theodore, J., ‘‘HeartLung and Lung Transplantation for Cystic Fibrosis,’

Clinical Re~fie~*s in Allergy 9(1-2):231-247, 1991.

Lloyd-Still, D. M., and Lloyd-Still, J. D., “The Patient, the Family, and the Community, ’ Texrbook of

Cyslic Fibrosis, J.D. Lloyd-Still (cd.) (Boston, MA:

John Wnght-PSG Inc., 1983).

MacLusky, I., McLaughlin, F. J., and Levison, H. R.,

“Cystic Fibrosis: Part I,” Current Problems in

50.

51.

52.

53.

54,

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

Pediatrics, J,D. Lockhart (cd.) (Chicago, IL: Year

Book Medical Publishers, 1985).

Mador, J. A., and Smith, D. H., “The Psychosocial

Adaptation of Adolescents With Cystic Fibrosis, ”

Journal of Adolescent Health Care 10:136-142,

1988.

McElvaney, N. G., Hubbard, R. C., Birrer, P., et al.,

“Aerosol Alpha- 1-Antitrypsin Treatment for Cystic

Fibrosis,” Luncet 337:793-798, 1991.

McPherson, L., Cystic Fibrosis Foundation, Bethesda, MD, personal communication, November

1991.

Naylor, E. W., Jr., “New Technologies in Newborn

Screen ing,” Yale Journal of Biolog) and Medicine

64:21-24, 1991.

Orenstein, D. M,, Cystic Fibrosis: A Guide for Patient

and Family (New York, NY: Raven Press, Ltd.,

1989).

Orenstein, D. M., Cystic Fibrosis Center, University

of Pittsburgh School of Medicine, Pittsburgh, PA,

personal communication, December 1991.

Ranieri, E., Ryan, R. G., Morris, C. P., et al., “Neonatal Screening Strategy for Cystic Fibrosis Using

Immunoreactive Trypsinogen and Direct Gene

Analysis, “ British Medical Journal 302: 1237-1240,

1991,

Rigot, J.-M., Lafitte, J.-J., Dumur, V., et al., ‘‘Cystic

Fibrosis and Congenital Absence of the Vas Deferens,’ New England Journal of Medicine 325:64-65,

1991.

Rose, M., Genentech, Inc., Washington, DC, personal communication, January 1992.

Rosenfeld, M. A., Yoshimura, K,, Trapnell, B. C., et

al., ‘‘In Vivo Transfer of the Human Cystic Fibrosis

Transmembrane Conductance Regulator Gene to the

Airway Epitheliums, ’ Cell 68: 143-155, 1992.

Shak, S., Genentech, Inc., San Francisco, CA,

personal communication, September 1991.

Shak, S., Capon, D. J., Hellmiss, R., et al., ‘ ‘Recombinant Human DNase I Reduces the Viscosity of Cystic

Fibrosis Sputum, ” Proceedings of the National

Academy of Sciences, USA 87:9188-9192, 1990.

Shapiro, B. L., and Heussner, R. C., Jr., A Parent’s

Guide to Cystic Fibrosis (Minneapolis, MN: University of Minnesota Press, 1991).

Sheperd, S. L., Melbourne, F. H., Harwood, I. R., et al.,

‘‘A Comparative Study of the Psychosocial Assets of

Adults With Cystic Fibrosis and Their Healthy

Peers,” Chest 97:1310-1316, 1990.

Spitzer, W. O., Suissa, S., Ernst, P., et al., “The Use

of &Agonists and the Risk of Death and Near Death

From Asthma,” Neu’ England Journal of Medicine

326:501-506, 1992.
82 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

65. Trezise, A. E., and Buchwald M., “In Vivo CellSpecific Expression of the Cystic Fibrosis Transmembrane Conductance Regulator, ’ Nature 353:434-

437, 1991.

66. Trulock, E. P., Cooper, J, D., Kaiser, L. R., et al., “The

Washington University-Barnes Hospital Experience

With Lung Transplantation, ’ Journal of the American Medical Association 266: 1943-1946, 1991.

67. Tsui, L.-C., and Buchwald, M,, “Biochemical and

Molecular Genetics of Cystic Fibrosis,’ Advances in

Human Genetics, vol. 20, H. Harris and K. Hirschorn

(eds.) (New York, NY: Plenum Press, 1991).

68. Valverde, K. D., Cystic Fibrosis Center, St. Vincent’s

Hospital and Medical Center, New York NY,

personal communication, February 1992.

69. Vemcai, R. L., ‘‘FDA Announces Faster Approval for

Breakthrough Drugs,” Associated Press, Apr. 9,

1992.

70. Wilfond, B., Gregg, R., Laxova, A., et al., “Mutation

Analysis for CF Newborn Screening: A Two-Tiered

Approach,’ Pediatric Pulmonology 1991 North

American Cystic Fibrosis Conference 6(Supp.):238,

1991.

71. Williams, C., Weber, L., and Williamson, R.,

“Guthrie Spots for DNA-Based Carrier Testing in

Cystic Fibrosis, “ Luncet 2:693, 1988,

72, Wine, J. J., “No CITR: Are CF Symptoms Milder?,”

Nature Genetics 1:10, 1992.

73. Wine, J.J., ‘‘The Mutant Protein Responds,’ Nature

354:503-504, 1991.
Chapter 4

The State-of-the-Art in Genetics
Contents

Page

BASIC GENETIC PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Function and organization of DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

DNA Replication.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . 85

Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Genetics and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

Modes of Inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

THE GENETICS OF CYSTIC FIBROSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

The Cystic Fibrosis Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Mutations in the Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Correlation Between Genotype and Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

TESTS FOR CYSTIC FIBROSIS MUTATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Techniques Used in Direct DNA Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Carrier Assays for Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Automation of DNA Diagnostic Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

RESEARCH FUNDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Federal Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Private Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

CHAPTER 4 REFERENCES .. .. .. .. .. .. .. .. .. .. .. . . . . . . . . . . . . . . . . . . . . . . 103

Boxes

4-A. The Gene Product: Cystic Fibrosis Transmembrane Conductance Regulator . . . . . 93

4-B. Gene Therapy and Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . 94

4-C. The Polymerase Chain Reaction: Step-by-Step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Figures

4-1. The Structure of DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

4-2. Chromosome Complement of a Normal Human Female . . . . . . . . . . . . . . . . . . . . . . . . . 87

4-3. DNA Replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

4-4. Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

4-5. Modes of Inheritance of Single Gene Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

4-6. Inheritance of Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

4-7. The Cystic Fibrosis Gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

4-8. Trchniques for DNA Analysis of Cystic Fibrosis Mutations . . . . . . . . . . . . . . . . . . . . 96

4-9. Reverse Dot Blot Analysis for Six Common Mutations . . . . . . . . . . . . . . . . . . . . . . . . . 99

Tables

4-1. Incidence of Cystic Fibrosis Among Live Births in the United States . . . . . . . . . . . . 90

4-2. Federal Extramural Funding for Cystic Fibrosis Research, Fiscal Year 1991 . . . . . . 102
Chapter 4

The State-of-the-Art in Genetics

Molecular biology is being integrated into genetics and medicine at a rapid pace. In the laboratory,

more than 300 human conditions can be analyzed

with today’s molecular genetic technology (3 1).

With clinical application of these discoveries comes

public expectations for new means of diagnosis,

screening, and even cure. This chapter provides an

overview of the genetic principles important to

understanding the issues involved in carrier screening for cystic fibrosis (CF). It outlines basic tenets of

human genetics and molecular biology and summarizes the technical aspects of CF carrier screening,

Finally, this chapter looks forward, exploring how

advances in automation could affect both carrier

screening for CF and testing and screening for

additional genetic disorders. Earlier OTA reports

provide further background in human genetics and

biotechnology (128-134).

BASIC GENETIC PRINCIPLES

Genetics explores how specific traits are passed

from one generation to the next. Except for certain

specialized cells, each of the trillions of cells in a

human being contains a complete set of genetic

instructions-the genome—for the individual. A

person’s genome governs everything from the structure of a single molecule, such as a protein, to the

expression of identifiable traits, such as eye color.

An intricate hierarchy of instructions determines

which cells act on this genetic information, as well

as when they do so.

Scientists study human genetics on many levels.

They assess, for example, the molecular basis for

inheritance by ex amining the specific structure and

function of the genetic material, DNA. Geneticists

also observe how the environment influences the

expression of genetic traits, and trace the clustering

of biological characteristics in populations.

Function and Organization of DNA

As in all higher organisms, genetic information is

stored in humans in DNA, a double stranded

structure resembling a twisted ladder. This double

helix consists of a genetic alphabet of four different

nucleic acid molecules, or bases—adenine (A),

thymine (T), guanine (G), and cytosine (C)---each of

which is attached to a deoxyribose sugar group and

a phosphate molecule (figure 4-l). The bases pair

predictably—A with T, and G with C—to form the

DNA double helix structure.

Lengths of DNA ranging from 1,000 to 2 million

base pairs comprise a gene, the fundamental physical and functional unit of heredity. About 50,000 to

100,000 structural genes, spread over 3,3 billion

base pairs, make up the human genome. DNA

associates with proteins to form chromosomes,

tightly coiled structures located in the cell nucleus.

In humans, genes are arrayed on 46 chromosomes22 pairs of autosomes and 1 pair of sex chromosomes (figure 4-2). Females have two X chromosomes, and males have one X and one Y chromosome. Egg and sperm cells contain just one copy of

each chromosome; fusion of the sperm and egg at

fertilization creates a full genetic complement.

The physical location of a gene on a chromosome

is called its locus. Some genes have been mapped—

plotted at a specific locus on a chromosome--and

cloned-generated in multiple copies in the laboratory. Alternative forms of a gene at a particular locus

are called alleles. At each locus along pairs of

autosomes, an individual can have two identical or

two different alleles, one copy inherited from the

mother and one from the father. If the alleles are the

same, the person is said to be homozygous for that

particular locus. If the versions differ, the person is

said to be heterozygous. Even though a normal

individual has at most two alleles at a given

locus-again, one copy inherited from the mother

and one from the father-additional alleles can exist

in other individuals.

DNA Replication

Through DNA replication, a full genome of DNA

is regenerated each time a cell undergoes division to

yield two daughter cells. In DNA replication, each

chain of the double helix is used as a template to

synthesize copies of the original DNA (figure 4-3).

During cell division, the DNA double helix unwinds, the weak bonds between base pairs break, and

the DNA strands separate. A series of enzymes insert

a complementary base opposite each base in the

original strand-A opposite T, and G opposite

-85-
86 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 4-l—The Structure of DNA

sugar. phosphate

backbone

Left: A schematic diagram of the DNA double helix. Right: The four bases form the letters in the alphabet of the genetic code. The sequence

of the bases along the sugar-phosphate backbone encodes the genetic information.

SOURCE: Office of Technology Assessment, 1992.

C--creating two identical copies of the original

DNA.

Proteins

The bridge between DNA’s chemical information

and physical realization of its instructions consists of

steps that convert the DNA code into biologically

active products. Through a process known as gene

expression, a DNA sequence for a structural gene

ultimately results in formation of a molecule called

a protein (figure 4-4). Proteins are required for the

structure, function, and regulation of all cells,

tissues, and organs in the body.

First, the bases in the DNA sequence are copied,

or transcribed, into messenger ribonucleic acid

(mRNA), a single-stranded molecule that carries the

genetic information out of the nucleus. The bases in

the mRNA are read as triplets, or codons, that

specify 1 of 20 different amino acids, the building

blocks of a protein molecule. Then, in accordance

with the instructions in the mRNA, amino acids are

assembled into a specific protein molecule. Thus,

the information encoded by DNA is transcribed to

mRNA and translated from the DNA code into a

protein that has a particular function in a cell.

Genetics and Disease

Hereditary variation is the result of changes-or

mutations—in DNA. Mutations present in germ

cells (egg or sperm) are inherited by offspring,

whereas those that occur in somatic cells (other body

cells) are not passed on to future generations. Most

mutations exist in both cell types. Mutations arise

from the substitution of one DNA base for another,

from rearrangements (e.g., small insertions or deletions) within the gene, or from duplication or

deletion of the entire gene. Approximately 4,000

known human disorders result from genetic causes

(88). Disorders arising from a mutation in only one

gene are known as monogenic. CF is a monogenic

condition.

Since proteins are produced from the instructions

in genes, a mutation in a gene that codes for a

specific protein can affect the structure, regulation,

function, or synthesis of the protein. A particular

mutation in a gene can produce a benign or mild

effect, while a different mutation in the same gene
Chapter &The State-of-the-Art in Genetics . 87

Figure 4-2-Chromosome Complement of a Normal Human Female

r,

4

19

SOURCE: Genetics & IVF Institute, Fairfax, VA, 1990.

can result in gross reduction or complete loss of

activity of the resulting protein. The genetic constitution of an individual is its genotype, while the

observable expression of the genes is its phenotype.

Modes of Inheritance

Although DNA’s structure was first determined i n

1953, the inheritance of genetic traits was studied

long before then. In 1865, Austrian monk Gregor

Mendel postulated that discrete biological units—

later named genes—were responsible for both the

maintenance and variation of certain characteristics

from one generation to the next. Since then, understanding of the

been refined.

In human

processes underlying inheritance has

monogenic—i.e., single gene—

disorders, the altered gene can be on any one of the

22 autosomal chromosomes or on a sex chromosome. Traditionally, modes of inheritance are

classed in three basic categories:

● autosomal dominant,

● autosomal recessive, and

● X-linked.

In the past decade, several less common heredity

pattems-e.g., genomic imprinting and mitochondrial inheritance-have been identified in humans

and tied to specific diseases such as Fragile X

syndrome and some respiratory enzyme deficiencies

(55,85,104).

In an autosomal dominant disease, a single mutant

allele causes the trait to be expressed, even though

the corresponding allele is normal. A heterozygous

individual with a mutation usually is symptomatic at

some level, although many disorders, such as

neurofibromatosis, vary in the severity and age of

onset of the condition. Marfan syndrome, Huntington disease, and adult polycystic kidney disease are

inherited in an autosomal dominant manner. Every

affected individual generally has an affected parent

(except for cases arising from a spontaneous, or de

novo, mutation). If the affected individual has an

unaffected spouse, each potential child will have a
88 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 4-3-DNA Replication

When DNA replicates, the original strands unwind and serve as

templates for the building of new, complementary strands. The

daughter molecules are exact copies of the parent, each daughter

having one of the parent strands.

SOURCE: Office of Technology Assessment, 1992.

50 percent chance of inheriting the mutant allele and

having the disease, and a 50 percent chance of not

inheriting the mutant allele (figure 4-5). Male and

female offspring are equally likely to inherit the

mutation. Barring de novo mutations, children who

do not receive the abnormal allele will not have the

disorder and cannot pass it on to future generations.

Recessive traits result in illness only if a person

has two mutant copies of the gene. That person is

said to be homozygous for the gene. Heterozygous

carriers of a single copy of the defective gene are

usually clinically asymptomatic. CF is inherited in

an autosoma1 recessive manner. Other common

disorders inherited this way include sickle cell

anemia, Tay-Sachs disease, phenylketonuria, and

ß-thalassernia. Individuals with the disease receive

one mutant allele from each parent, who are each

asymptomatic carriers. When both parents are carriers of a recessive trait, each potential son or daughter

has a 1 in 4 chance (25 percent) of inheriting the

mutant gene from both parents, resulting in the

homozygous affected state (figure 4-5). Each potential child also has a 50 percent chance of inheriting

one mutation from either parent, thus being an

unaffected carrier. They, in turn, can pass on the

mutation to their children. Finally, each potential

child of two carriers also has a 25 percent chance of

inheriting the normal allele from both parents, thus

being a homozygous unaffected individual who

cannot pass on the mutation to future offspring.

In sex-linked disorders, the mutant gene can

theoretically be on either sex chromosome, the X or

the Y. In reality, the Y chromosome is small and

contains few genes. To date, no known disease

conditions transmit via the Y chromosome in

humans. The X chromosome, however, is large and

contains numerous genes for many traits that can be

mutant and result in disease. Diseases caused by

aberrations in genes on the X chromosome are called

X-linked disorders. Duchenne muscular dystrophy

and hemophilia A and B are X-linked conditions.

Genes on the X chromosome can also be dominant

or recessive, but because females have two X

chromosomes, and males have one X and one Y,

male and female offspring show different patterns of

inheritance. Sons of a carrier female-who is often

asymptomatic —have a 50 percent probability of

inheriting the mutant gene from their mother. These

sons will be affected (figure 4-5). Sons who do not

inherit the abnormal gene are unaffected and cannot

transmit the gene. Daughters of a carrier mother each

have a 50 percent chance of inheriting the defective

gene-thus being unaffected carriers-and a 50

percent chance of not inheriting the gene and being

unaffected noncarriers. A male with an X-linked

recessive condition will transmit the gene to all of

his daughters, who will be carriers, but to none of his

sons, who will be unaffected. An X-linked dominant

disease affects the mother, who can also pass it on to

both her sons and daughters with a 50 percent

chance. Affected males pass X-linked dominant

conditions to all of their daughters, but not their

sons. X-linked dominant diseases are relatively rare.
Chapter 4---The State-of-the-Art in Genetics ● 89

Figure 4-4-Gene Expression

)

I

CYTOPLAS M

Free Amino Acids

RIBOSOME

SOURCE: Office of Technology Assessment, 1992.

Figure 4-5-Modes of Inheritance of Single Gene Disorders

X-linked recessive

r---l 11--- n

I
90 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

THE GENETICS OF CYSTIC

FIBROSIS

Table 4-1—incidence of Cystic Fibrosis Among

Live Births in the United States

As mentioned earlier, CF is an autosomal recessive disorder. To have CF, an individual must inherit

a mutant CF gene from each parent. If a couple

produces a child with CF, each parent (excluding the

possibility of a new mutation, nonpatemity, or a rare

genetic event called uniparental disomy) must possess one of the 170+ CF mutations, but not

necessarily the same ones. Each parent, then, is an

asymptornatic carrier. For these couples, the chance

of having a child with CF is 1 in 4 for each pregnancy

(figure 4-6). Furthermore, if two carriers have an

unaffected child, there is a 2 in 3 possibility that the

unaffected child is a carrier. Again, because CF is an

autosomal recessive disorder, it equally affects

males and females.

CF occurs in all racial and ethnic groups, although

more frequently in some than in others (table 4- 1). It

is the most common, life-shortening, recessive

genetic disorder in Caucasians of Northern and

Central European descent. In the United States, the

incidence of CF in Caucasians is about 1 in 2,500

live births (17,56,81). An incidence of 1 in 2,500

Figure 4-6-inheritance of Cystic Fibrosis

o Carrier parents o

SOURCE: Office of Technology Assessment, 1992.

Population Incidence (births)

implies a carrier frequency of approximately 4

percent. In other words, 1 in 25 Caucasians in the

United States—about 8 million Americans—

possess 1 chromosome with a CF mutation and 1

chromosome with a normal CF gene, and hence are

carriers.

In 1989, the gene responsible for CF was isolated

and precisely located among the 22 autosomes, its

most common mutation identified, and its DNA

sequence determined (74,101,107). Prior to this

discovery, the CF gene was localized to a specific

chromosom---chromosome 7-by examining markers in the area of DNA believed to surround the gene.

Using a technique known as restriction fragment

length polymorphism (RFLP) analysis, scientists

could follow a DNA pattern of inheritance through

a family. The DNA pattern itself was not the CF

gene, but was close in location-r linked-to it.

This method of linkage analysis enabled researchers

to hone in on the exact location of the gene on

chromosome 7 (77,125,126,137,143). While some

of the underlying problems in CF could be studied

with linkage analysis, the exact identification of the

gene opened up new avenues of pursuit in understanding the nature of the biochemical defect, in

elucidating possibilities for treatment and cure, and

in developing assays to detect carriers of CF

mutations.
Chapter 4--The State-of-the-Art in Genetics . 91

The Cystic Fibrosis Gene

The CF gene is located on the long arm of

chromosome 7, where it is distributed over 250,000

base pairs (250 kb) of genomic DNA (figure 4-7). At

this locus, regions of the gene that code for the CF

protein product are separated into 27 fragments, or

exons, interspersed with portions of DNA that do not

get translated-i. e., stretches, called introns, that are

not decoded into proteins. During a process called

transcription, introns are spliced out and the exons

are pieced together into a precisely ordered string of

6,100 base pairs that codes for a protein comprised

of 1,480 amino acids (74,101 ,107).

Ultimately, the CF gene product—known as the

cystic fibrosis transmembrane conductance regulator (CFTR)--links DNA instructions with a critical

biochemical function. When the CFTR comes from

a mutant CF gene, that function is impaired and

produces the medical manifestations of the disorder

(box 4-A). The exact biochemical malfunction

responsible for CF remains unknown, but CFTR

regulates chloride ion (Cl-) conductance in affected

cell types and appears to be a Cl - channel (the

structure that governs Cl- entry and exit in the cell).

Efforts to understand the underlying pathogenesis of

CF, and to develop treatment for it, focus on the

structure and function of the protein product (30). In

particular, studies of CFTR examine its role in ion

transport, the key disturbance in the disorder. One

major avenue of intervention under development is

gene therapy, which involves inserting DNA that

codes for CFTR into cells with mutant CF alleles in

order to restore physiological function (box 4-B).

Mutations in the Gene

Concomitant with the elucidation of the CF gene

was the identification of a three base-pair deletion

that resulted in a faulty CF gene product (i.e., a

flawed CFTR). This mutation—abbreviated as

DF508—results in the deletion of one amino acid,

phenylalanine, at position number 508 in CFTR.

Approximately 70 percent of all mutant CF genes in

Caucasians in the United States and Canada exhibit

this mutation (74,81). However, international studies reveal ethnic and regional variation in the

distribution of this mutation (36,105). Overall, the

DF508 mutation is most frequent in Northern

European populations and less prevalent in persons

from Southern Europe. Not surprisingly, the multicultural nature of the United States and Canada

reflects this variation. The international epidemiology of the DF508 mutation is summarized in

appendix A, as is the ethnic distribution of the

mutation in the United States.

No other mutation accounts for a similarly large

fraction of mutant CF genes among the remaining 30

percent of CF gene defects. To date, more than 170

additional mutations have been identified, and the

number continues to grow (30). Most of these appear

only in single individuals or families, although a few

mutations account for 1 to 3 percent of CF mutations

in the United States. The more common CF mutations and their epidemiology are also described in

appendix A; some of these lesions also appear to

vary among populations. Among Jewish persons of

Central and Eastern European descent (Ashkenazic

Jews), DF508 is relatively rare, but one mutation,

W 1282X, accounts for approximately 60 percent of

CF mutations in this group (1 14).

Correlation Between Genotype and Phenotype

The severity of CF symptoms differs greatly

among individuals. To some extent, this is due to

DNA differences and resultant alterations in the

CFTR protein. Some mutations correlate with particular symptoms—primarily status of pancreatic

enzyme sufficiency—and can be considered either

mild (conferring pancreatic enzyme sufficiency) or

severe (conferring pancreatic enzyme insufficiency)

for this criterion (7,1 1,19,20,25,38,74,76,78,110-

114,1 16,124). DF508 is considered a severe mutation, generally resulting in pancreatic insufficiency

in homozygotes or in conjunction with a different

severe defect in the other CF gene, although some

exceptions exist (20,74,76,78,1 10-1 12,124). Other

mutations appear to correlate with milder clinical

outcome, but more data need to be collected

(11,25,78,1 13,1 16). Pancreatic sufficient patients

tend to have better respiratory function.

Pulmonary function generally does not correspond to specific mutations (74,78,1 10-1 12,124).

Correlations between other mutations and particular

phenotypes are also being studied (1 1,33,44,91,

99,1 19,124,145). Overall the course of the disease

depends on both genetic and environmental features,

and complete clinical outcome cannot be predicted

on the basis of DNA analysis alone.
92 ● cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 4-7—The Cystic Fibrosis Gene

Chromosome 7

6a 15 17a

6b

23

17b

50 1000 125 150 200

The CF gene is located on the long arm of chromosome 7, where it is spread over 250,000 base pairs

(250 kb) of DNA. Coding regions of the DNA, or exons, are separated by noncoding regions, or introns.

After the DNA is transcribed into messenger RNA (mRNA) comprised of all 27 exons of the gene, the

mRNA is exported from the cell nucleus. Finally, instructions in the mRNA are translated, using special

structures in the cell to assemble 1,480 amino acids into the final protein product.

250

(kb)

SOURCE: Office of Technology Assessment, 1992, based on M.C. Iannuzzi and F.S. Collins, “Reverse Genetics and

Cystic Fibrosis,” American Journa/ of Respiratory Cellular and Molecular Biology 2:309-316, 1990.
Chapter 4---The State-of-the-Art in Genetics ● 93

Box 4-A—The Gene Product: Cystic Fibrosis Transmembrane Conductance Regulator

Since the discovery of the principal mutation responsible for cystic fibrosis (CF), scientists have begun to relate

this DNA error to the defect in ion transport long known to characterize the disorder. Cells cannot pump water, but

must move fluids across their membranes through osmosis, a process that depends largely on ion movement either

through pores in the membrane (channels), or transport systems designed to convey ions from one side of the

membrane to the other. In CF affected individuals, regulation of chloride ion (Cl-) transport is defective

(46,95,140,142). Like most cellular activities, Cl- movement requires communication among different parts of the

cell. Intricate networks of messenger systems accomplish this. Two common mediators of these systems, calcium

ions (Ca2+) and cyclic adenosine monophosphate (cAMP), regulate Cl- channels in epithelial cells. In individuals

with CF, channels regulated by Ca2+ function properly, but those channels controlled by cAMP and its

intermediaries do not (95).

The product of the CF gene, a protein called the cystic fibrosis transmembrane conductance regulator (CFTR),

regulates this cAMP-mediated Cl- conductance across the epithelial membrane. With current techniques, direct

observation does not reveal the structure of CFTR. Rather, increasingly detailed examination of the deficits

accompanying the defect, elucidation of the effect of conferring normal activity to CF cells, and speculations about

both structure and function of the molecule based on predictive modeling techniques and manipulation of the gene

are slowly providing insight into CFTR's nature.

Current research suggests that CITR functions as a Cl- channel (4,13,47,49,96,98,1 18), although it may have

other fictions as well (10,22,59). On the basis of predicted structure, CFTR might belong to a large family of

energy-dependent membrane transport systems that consists of several membrane-sparming regions and segments

that bind the cellular energy source, adenosine triphosphate, or ATP (2,49,58,59,65,93,100,122). Activation of

CFTR is mediated by a regulatory domain (3,27,98). The DF508 mutation and numerous other mutations are located

in regions that code for portions of the protein likely to be of functional importance (35,38,50,71,75,92,98).

Numerous experiments have established Cl- channel regulation by cAMP through introduction of the normal

CF gene into CFTR-defective epithelial cell lines (39,52,69,96,97,102). Moreover, Cl- conductance was induced

in nonepithelial cell lines-theoretically without previously existing Cl- channels-when the CF gene was

intre-heed, suggesting that CFTR might be a channel (4,5,72,106). Conversely, Cl- conductance was blocked in

normal cells by preventing production of the CFTR product (1 15). However, recent discoveries of new types of

chloride channels in CF-affected tissues complicate a straightforward interpretation that CFTR is a chloride channel

(121,135).

Scientists are attempting to correlate symptoms of CF with a single molecular cause. CFTR has been

demonstrated in all organs affected by the condition (123). One hypothesis to explain the multitude of CF traits

attributes multiple symptoms to improper modification of a host of non-CFTR proteins due to decreased Clpermeability in cells of CF patients (8,141).

As the workings of CFTR are better understood, new avenues for treatment open. If the underlying causes of

the disease are understood therapies can be directed at correcting the molecular deficits. For example, administering

large quantities of cAMP analogs elicits Cl- conductance in cells with mutant CFTR (37,40,144). This suggests

cAMP analogs might be an effective pharmacological intervention.

Elucidation of the structure and function of the CFTR protein could facilitate a means of assaying for CF

mutations that would not require DNA analysis and the need to examine multiple mutations. Such a functional test

theoretically would measure either the presence, absence, or altered state of the protein product. A functional test

might, for example, evaluate Cl- conductance. Indications that Cl- conductance can be induced in cells with CF

mutations, but with a recognizably different pattern than normal cells, might enable such a test (37,40). This pattern,

however, appears to differ among cell types and methods of measurement (4,144). Likewise, understanding the

extent to which protein processing is affected remains elusive (26,37,40,147). Although knowledge about the nature

of CFTR and its structure and fiction continues to advance rapidly, answers that would render feasible a functional

test for CF carriers are lacking. It might be, for example, that the more than 170 different CF mutations lead to a

range of activities at the cellular level.

SOURCE: Office of Technology Assessment, 1992.
94 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 4-B-Gene Therapy and Cystic Fibrosis

Recent advances have moved gene therapy from theory to clinical and therapeutic experimental application

(6,57). Protocols for gene therapy in humans must be approved by the Recombinant DNA Advisory Committee

(RAC) of the National Institutes of Health (NIH), the NIH director, and the Food and Drug Administration in what

can be a lengthy process, although the procedure has been streamlined (48). The first human gene therapy clinical

trial was approved by the RAC and the NIH director in July 1990. By June 1992, nine other protocols for human gene

therapy were in various stages of approval (146). For gene transfer---experiments that mark cells to trace the course

of a treatment or the disease but are not therapetic--- additional 15 protocols were in various stages of approval

(146). Current human gene therapy trials include alteration of:

. white blood cells to treat a rare genetic disorder, severe combined immune deficiency due to adenosine

deaminase deficiency, begun in September 1990 (84);

● immune system cells to produce an anticancer agent, begun in January 1991 (21,62); and

● liver cells to correct hypercholesterolemia, a genetic disorder of fatal cholesterol buildup, approved in October

1991, begun in June 1992 (56 FR 58800; 146).

The theory of gene therapy is straightforward: The normal gene is inserted into the cellular DNA either to code

for a functioning protein product, or, in the case of cancer thempies, to confer disease-fighting properties.

Experimentally, delivering normal genes into desired cells can be accomplished through physical or chemical means

that disturb the cell membrane and allow DNA to enter, including specially modified viruses, liposomes (fatty

materials able to transport drugs directly into cells), and direct injection (43,136). Somatic cell therapy-the only

approach approved for human trials---changes only the DNA of the person receiving the therapy and cannot be

inherited by offspring. In contrast, germ line gene therapy would alter the genetic material that is passed onto future

generations. To date, no germ line therapy in humans has been proposed. For most conditions, cells are removed from

the patient, genetically altered, and replaced.

Correction of abnormal Cl- transport through insertion of the normal CF gene into defective cells suggested that

gene therapy was a viable consideration for treating CF (39,52,97,102); currently, the respiratory deficits of the

disease are being targeted for correction by gene therapy. Unlike the RAC-approved protocols in progress, however,

lung cells are generally inaccessible for removal and redelivery after gene transfer, making other means of

administering the DNA necessary. Several systems are under investigation for efficacy of delivery in vivo without

side effects. In one system, DNA is removed from an adenovirus, the type of virus responsible for some forms of the

common cold and other respiratory ailments, and the inactivated virus shell is used as a vector to deliver the CF gene

directly into the lungs of rats (108,109). The CF gene has also been delivered into cells isolated from the lungs of

CF patients by bronchial brushing (32). In vivo and in vitro, significant amounts of messenger RNA for the CF gene

are still present 6 weeks later, suggesting that long-term expression of the gene will be feasible. It is not yet known,

however, how frequently new doses of the CF gene would have to be administered (32,109). An alternative delivery

mechanism, aerosolized liposomes, has been used to deliver alpha- 1-antitrypsin genes into rabbit lungs (61). A s imilar

system might be applicable to delivery of the CF gene to human lungs.

Many questions about the safety and efficacy of gene therapy for CF must be answered before it will be suitable

for human trials (30,32,138,146). Scientists do not yet know how much corrected protein product is needed to restore

normal function to a patient with CF. Neither do they know whether adverse health effects will result from placing

too much CFTR in a patient. Further, even though the virus has been fully debilitated in theory, using a viral vector

raises concerns about expression of contaminating normal virus. Crippled viruses could also join with genetic material

already in the cell and allow expression of a new virus or activate cells to a cancerous state.

Ethical considerations are also raised by some (6). Because gene therapy involves altering the genetic makeup

of an individual, some express concerns about eugenic overtones, although only somatic cell therapy is under

consideration. The general public, however, is enthusiastic. A 1986 OTA survey found that 83 percent of the

American public approved of human cell manipulation to cure usually fatal diseases, 78 percent would be willing to

undergo gene therapy personally to correct a genetic proclivity to a serious or fatal disease, and 86 percent of

respondents would be willing to have his or her child undergo gene therapy for a usually fatal disease (131).

Gene therapy clearly offers the promise of treatment for some disorders. On the other hand, heightened attention

to genetics in general-and gene therapy in particular—in the popular press can raise false hopes for cures for diseases

long before they will be feasible or readily available (53,70). For CF, critical steps have been made towards the first

attempt at gene therapy in humans; clinical applications, however, are still on the horizon.

SOURCE: Office of Technology Assessment, 1992.
Chapter 4--The State-of-the-Art in Genetics ● 95

TESTS FOR CYSTIC FIBROSIS

MUTATIONS

Localization of the CF gene and determination of

its sequence enabled direct analysis of DNA for the

presence of CF mutations. However, as mentioned in

chapter 2, carrier screening is hindered by the

multitude of mutations, particularly those too rare to

be used practically in a CF carrier screening panel.

Moreover, not all CF mutations have been discovered. As additional mutations are elucidated and

incorporated into carrier screening protocols, the

detection limitation decreases incrementally, although the inability to detect all mutations remains.

This section explains the process and limits of direct

DNA screening as applied to CF.

Techniques Used in Direct DNA Analysis

Multiple techniques are used to analyze DNA.

Four principal processes are employed, though each

technique is not performed on all samples. These

methods, depicted in figure 4-8, are:

●

●

●

●

DNA amplification;

restriction enzyme digestion;

gel electrophoresis; and

Southern transfer, dot-blotting, and probe hybridization.

DNA Amplification

DNA amplification increases the amount of DNA

to be analyzed by making copies of the original

sequence from the sample. A process call the

polymerase chain reaction (PCR) is typically used

(box 4-C). Using PCR, selected areas of a gene can

be amplified through repeated cycles to yield large

quantities of the sample for rapid diagnosis.

While PCR amplifies a stretch of DNA between

two primers, a new technique known as ligase chain

reaction (LCR) amplifies only the region of DNA

directly beneath the known sequence. Like PCR,

millions of copies of the original sequence are made,

but LCR’S advantage is that it lends itself easily to

detecting mutations differing by even a single base

(82, 139 )---although it is not yet practical for general

use.

Restriction Enzyme Digestion

Restriction enzymes act as molecular scissors,

cutting the DNA into fragments at specific sequences. Different enzymes recognize and cut different sequences. Mutations in a gene alter the DNA

sequence and sometimes create or destroy specific

sequences known as restriction sites. Thus, when

changes occur in the DNA, restriction enzyme

digestion can yield different sizes of DNA fragments

in samples taken from an affected versus an unaffected individual. To distinguish between alleles, a

restriction enzyme site can be intentionally created

if a mutation has not created one (45,54).

Gel Electrophoresis

In gel electrophoresis, PCR-derived or restriction

enzyme digested DNA is separated into its different

sized fragments. The sample is placed in a semisolid

matrix, called a gel, and exposed to an electric field.

In response to the electrical field, the DNA migrates

toward one edge of the gel. In doing so, the gel acts

as a sieve, with large DNA fragments passing

through the gradient more slowly than small ones,

allowing the DNA mixture to be separated according

to size.

After gel electrophoresis is performed, the fragments can either be viewed directly using ultraviolet

light plus a dye called ethidium bromide, or transferred onto a membrane for analysis with specific

DNA probes (deseribed in the following section).

Southern Transfer, Dot Blotting, and Probe

Hybridization .

DNA fragments from gel electrophoresis can be

transferred to a nylon or other type of membrane,

forming a “Southern blot. ” A specitic probe---or 

short sequence of single-stranded DNA complementary to the DNA sequence being sought--can be

washed onto a membrane, where it will bind to

complementary sequences on the membrane. Although most probes are generic and identify all

alleles of a gene, allele specific oligonucleotide

(ASO) probes refine diagnostic accuracy by perfectly matching the nucleotide sequence of a portion

of the gene in question (24). Sequences differing by

only one base can be detected. Before use, the probe

is labeled with a fluorescent or radioactive marker so

the region of DNA binding to the probe can be

detected. The hybridized molecules can be viewed

either by exposure to x-ray film for a radioactive

probe or by other methods, such as colorimetric

dyes.

A variation of Southern transfer, called dot

blotting, involves directly spotting DNA into discrete spots on the nylon membrane. A probe, or
96 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 4-8-Techniques for DNA Analysis of Cystic Fibrosis Mutations

Intact DNA is chemically

extracted from the sample

ENZYMES (v)

act like molecular scissors

and cut the DNA into fragments

Each individual restriction

I enzyme cuts at its own

AMPLIFICATION

(Molecular photocopying of DNA) \

Multiple copies of DNA sample \

DOT BLOT

floated in a color developer

or if a radioactive probe is

used exposed to x-ray film

There are over 170 mutations at the cystic fibrosis

locus (the most common mutation is DF508)

REVERSE DOT BLOT

SOURCE: Office of Technology Assessment, 1992.
Chapter 4--The State-of-the-Art in Genetics ● 97

Box 4-C—The Polymerase Chain Reaction: Step-by-Step

For the most part, all body cells within an individual contain the same DNA. Thus, DNA molecules in cells must

regenerate copies of themselves each time a cell divides; DNA reproduces through a process called replication. During

replication, the original strands in the DNA double helix unwind and serve as templates for the building of new,

complementary strands, resulting in two identical copies of the original DNA molecule.

The polymerase chain reaction (PCR) is an in vitro technology based on the principles of replication. First described

in 1985, PCR is now widely performed in research and clinical laboratories, and it is a critical technology for DNA

diagnostics.

PCR involves the repeated duplication of a specific area of DNA to increase the amount of that DNA available to

be used for research or test purposes. For example, consider the following sequence of double-stranded DNA to be

amplified using PCR:

[-G-G-C-T]

-T-T-C-G-A-T-G-G-A-T-A-A-A-C-C-G-A

-A-A-G-C-T-A- C-C-T-A-T-T-T-G-G-c-T

[-T-T-C-G-]

In order to perform PCR, the sequences of the DNA at both ends of the region of interest must be known, and their

complementary sequences available as short pieces of purified DNA called primers. One primer must be complementary

to the end of one strand, the second to the opposite end of the other strand as indicated in the diagram above. These two

specific sequences flank the area the scientist wants to copy, and serve as the foundation to which bases can be added

and the DNA strand copied.

In PCR, the temperature of the solution centaining the DNA to be amplified is raised to about 95 ‘C, which results

in the separation, or melting, of the double helix to yield single-stranded pieces:

-T-T-C-G-A-T- G-G-A-T-A-A-A-C- C-G-AThe scientist then sets conditions in the reaction that allow new copies of the DNA of interest to be synthesized from

the ends of the primers (referred to as primer elongation). That is, DNA polymerase (a heat-stable version of an enzyme

from Thermus aquaticus, a thermophilic microorganism isolated from a hot spring in Yellowstone National Park) starts

at the end of the primers and, using bases (G, A,T,C) that are part of the reaction mixture, synthesizes complementary

strands of each of the two single strands to yield two strands from the original one:

-T-T-C-G-A-T- G-G-A-T-A-A-A-C-C-G-A

-A-A-G-C-T-A-C- C-T-A-T-T-T-G-G-c-T---

---T-T-C-G-A-T-G- G-A-T-A-A-A-C-C-G-A-

-A-A-G-C-T-A-C-C-T-A-T-T-T-G-G-C-TThus one cycle of PCR occurs, doubling the number of DNA copies from the original area of interest. After this

frost round of synthesis, and for each subsequent cycle, the temperature of the reaction is raised to approximately 95 oC

to separate the DNA strands. Primers are again allowed to hybridize to the strands, and DNA synthesis allowed to occur.

After a second cycle of PCR, the two strands become four, and after 20 to 25 cycles of PCR, the original DNA area of

interest has been amplified about a millionfold.

SOURCE: Office of Techology Assessment, 1992.
98 ● Cystic Fibrosis and DNA Tests: Implication.Y of Carrier Screening

probes, can be hybridized to the membrane and

diagnosis made rapidly (42). Reverse dot blotting is

similar in principle to Southern transfer and dot

blotting. However, in reverse dot blotting, the

unique ASOs (which would be used as probes in

conventional Southern analysis or dot blotting) are

immobilized on the membrane. Key segments of the

individual’s uncharacterized DNA are then amplified, labeled, and hybridized to the probes on the

membrane.

Carrier Assays for Cystic Fibrosis

CF carrier tests involve direct DNA analysis, and

all laboratories currently performing them directly

analyze the gene. In individuals with a family history

of CF or an affected child, an indirect assay-ailed

linkage analysis-sometimes can be used to obtain

additional information in the event of a negative test

result. The following sections describe the techniques used to detect CF mutations.

Direct Analysis of the Cystic Fibrosis Gene

DNA is generally obtained from white blood cells

in blood samples, although it can be obtained from

almost all nucleated cells in the body. Some groups

in the United Kingdom and one project in the United

States use buccal cells from mouthwash samples (ch.

10). In 1992, most laboratories in the United States

assay DNA samples for the DF508 mutation and 6 to

12 other common mutations (DF508+6-12). Some

laboratories screen for additional mutations.

After DNA is extracted from a blood sample, key

segments containing mutations are amplified with

PCR. When multiple segments are arnplified at

once, it is referred to as multiplexing. For some of

the mutations, the amplified DNA can be electrophoresed and the migration pattern-specific to

each mutation—visualized directly on the gel.

Digestion with restriction enzymes followed by gel

electrophoresis and visualization, or blotting followed by ASO hybridization, can also be used to

analyze the mutations.

Reverse dot blotting using ASOs can be used to

simultaneously analyze multiple CF mutations, and

test kits that do so are under development in the

United States (42) (figure 4-9).

The Limits of DNA-Based Tests

DNA analysis for CF is limited by the diversity of

mutations and the variation in frequency among

different racial and ethnic groups (34). At present,

DF508+6-12 other mutations account for approximately 85 to 95 percent of all mutant CF genes in

Caucasians, depending on ethnicity (14,89), The

range in detection rates presented by different

commercial vendors likely results from their using

tests that detect different mutations and assaying

different populations (29,66).

The presence of a specific mutation establishes

CF carrier status; a negative test, however, does not

preclude carrier status, since not all mutations are

known or assayed. About 5 to 15 percent of carriers

remain undetected because their mutation is not

included in the assay.

Linkage Analysis

In some cases where one partner is a known

carrier and the other does not test positive for the

most common mutations, linkage analysis can be

used to gather more information about an individual’s risk. Linkage analysis can only be performed in

families with living members with CF or on DNA

samples stored from a deceased individual; frequently, such samples are unavailable. In this

procedure, DNA markers are studied to trace the

transmission pattern in a particular family of the CF

gene and a specific mutation. For families with the

necessary DNA samples, linkage analysis is generally informative. In rare instances, recombination

events, which can alter marker patterns, can lead to

erroneous conclusions from linkage results.

Automation of DNA Diagnostic Procedures

The ability to test quickly and accurately will be

crucial to widespread, inexpensive CF carrier screening, particularly if batteries of genetic assays are to

be developed: Automation will be key. At present,

the Human Genome Project serves as the primary

impetus for automating DNA analysis, and the

National Laboratories engaged in this aspect of the

project are at the forefront in developing these

technologies (1,5 1,64,103). As such, most advances

in automated technology are specific to DNA

sequencing, not diagnosis. Facets of the two processes overlap considerably, however, and some

sequencing technologies can be made directly applicable to, or adapted for, DNA diagnosis.

Over the past few years, a number of instruments

have been developed to increase the speed and

volume of routine DNA diagnostic procedures (79).
Chapter 4--The State-of-the-Art in Genetics ● 99

Figure 4-9—Reverse Dot Blot Analysis for Six Common Mutations

F

F

F

F

F

F

F

F

G

G

G

G

c1

G

x

I

I

Allele specific oligonucleotide probes are bound to the test strip to detect six common CF mutations; in this photograph, each individual

strip runs horizontally. DNA samples from individuals of unknown CF status are PC R-amplified and hybridized to separate test strips. Here,

test strips for eight different individuals are shown (rows A through H). Following hybridization and colorimetricanalysis, the patterns of dots

on the strips are revealed-and hence the CF status of the individuals.

For each mutation on the strip (DF508, G542X, G551D, R553X, WI 282X, and N1303K) the left dot, if present, indicates the person has

a normal DNA sequence at t hat part of the CF gene. The right dot, if present, indicates the person has a CF mutation at that site. Individual

A, then, has no CF mutations at the loci tested, as demonstrated by single dots on the left side for all mutations. In contrast, individuals

B,D, F, and H are carriers, as demonstrated by the presence of two dots for one of the CF mutations. Individual C has CF, as demonstrated

by a single dot on the right side of the DF508 panel; individual E has CF, as demonstrated by the single dot on the right side of the G542X

panel. Individual G also has CF, but this person’s CF arises from two different mutations—DF508 and R553X—as indicated by the pairs

of dots in each of these panels.

SOURCE: Roche Molecular Systems, Inc., Emeryville, CA, 1992.

To the extent that the Human Genome Project is

federally funded, integration of existing technologies specifically for clinical diagnostics will depend

on Federal research priorities. Given the state of

already automated procedures used in diagnosis and

the rapid development of new DNA technologies

under the auspices of the Human Genome Project,

DNA automation is advancing at a pace that could

realize entirely automated DNA diagnosis in the

next few years.

Already, a nonelectrophoretic method of mutation

detection has been automated and applied to detection of DF508 (90). Most DNA diagnostic techniques, however, still depend on electrophoresis,

especially in the early stages of gene identification.

Currently, instrumentation for such DNA diagnosis,

except probe hybridization to a membrane, are

automated or being automated. At a minimum, these

steps include:

. DNA isolation from source material (e.g.,

blood, mucosal, or buccal cells),

. DNA amplification,

. gel preparation and loading for electrophoresis,

and

● Visualization and interpretation of results.

Automated instruments for DNA extraction, gene

amplification by PCR, sequence gel loading, and

visualization of sequence gel results already exist
100 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Photo mxlit: Tony J. Beugeisdijk, Los Alamos National Laboratory

Automated robotic system used in DNA analysis at Los

Alarms National Laboratory.

(42,51,64,79,103). While not faster than humans,

these machines are designed to standardize procedures and decrease human error. They are not,

however, always reliable (18,73,103). At Lawrence

Berkeley Laboratory, scientists are creating separate

robotic systems to allow simultaneous amplification

and analysis of 96 different samples (94,127). At Los

Alamos National Laboratory, a robotic system can

produce high-density falters that increase the amount

of information on one 96-sample filter by a factor of

16-i.e., 1,536 results can be obtained from one

filter (15). To visualize and interpret results, scientists have designed an image plate reader that

eliminates x-ray film (51,94,127).

Many new techniques for automated DNA analyses have been proposed, although at present they are

not viable for large-scale clinical application (51,60,

64). One new procedure, DNA sequencing by

hybridization, involves coating a DNA chip with

short pieces of known DNA to which DNA of

unknown sequence can be hybridized. Based on the

hybridization pattern, mathematical algorithms can

be used to decode the unknown sequence (923,51,64).

A technique known as flow cytometry sequences

DNA one molecule at a time by identifying individual, consecutive bases through base-specilic fluorescence (67,68,83). Several other approaches to increasing sequencing speed are under development,

including mass spectroscopy, atomic probe microscopy, and x-ray diffraction (28,51 ,64,79,103). As

DNA sequencing becomes more rapid and less

expensive, the prospect of determin ing CF (and

other) mutations by direct DNA sequence analysis

might someday be realized (86,87).

At present, most components of DNA analysis

necessary for DNA-based genetic tests are automated as individual units, though some scientists are

working on coordinating sequential steps into one

system (15,94,127). In Japan, HUGA-1, a fully

integrated robotic system that automates DNA

sequencing from purification of DNA to interpretation of the final sequence, was to begin operating in

April 1992 (41,64,1 17). Research into automation is

also being carried out in Europe (63,120).

Clearly, crucial steps in DNA-based carrier screening assays for CF are automated now in research

settings: DNA extraction, amplification, gel preparation, loading for electrophoresis, and visualization

and interpretation of results. Only the step where a

probe is hybridized to the membrane remains to be

automated. The availability of high density filters

means numerous DNA samples can be stored and

analyzed concurrently, suggesting improved methods for handling the quantity of samples in highvolume screening. While currently the procedures

are automated as single units, integrated robotic

systems are being developed. Taken together, these

advances in instrumentation indicate that automating the components of rapid carrier screening for CF

is already technologically feasible, although an

integrated system incorporating all of the processes

has yet to be created.

RESEARCH FUNDING

Federal finding for CF research is principally

through the National Institutes of Health (NIH).

Unlike most biomedical research, private-sector

funds, which are made available through grants by

the Cystic Fibrosis Foundation (CFF) and direct

conduct of research by Howard Hughes Medical

Institute (HHMI), account for a large portion of

CF-related research. Some investigators receive

funding through one or more of these sources. All

three sources fund basic biomedical research. NIH

and CFF support specific projects, while HHMI

awards salaries and research support to individual

investigators.

Federal Efforts

In fiscal year 1991, NIH allocated $46,937,000 for

all research related to CF. Of that, $20,662,724 was

provided for intramural research. Extramurally,
Chapter kThe State-of-the-Art in Genetics . 10I

$19,753,956 was granted to investigators for whom

CF is the primary focus of laboratory or clinical

research and an additional $6,520,320 to those for

whom CF research is a secondary component. Nine

of 12 institutes of the NIH and 3 of 4 research centers

apportion these monies. In fiscal year 1991, two

institutes-the National Institute of Diabetes and

Digestive and Kidney Diseases (NIDDK) and the

National Heart, Lung, and Blood Institute (NHLBI)--

accounted for 73 percent of Federal funding for

CF-related research: NIDDK disbursed $10,226,070

(39 percent) and NHLBI disbursed $8,847,051 (34

percent). One institute of the Alcohol, Drug Abuse,

and Mental Health Administration provided $66,236

in fiscal year 1991 for CF-related research as a

secondary research focus. Table 4-2 lists funding by

institute or center. The U.S. Department of Energy

(DOE) appropriated $48 million in fiscal year 1991

and $59 million in fiscal year 1992 for the human

genome initiative. Indirectly, technology development---e.g., in the form of automation of DNA

diagnostic technologies-horn DOE’s funding of

the Human Genome Project could affect DNA

diagnostics if it is determin ed to be a program

priority.

Beginnin g in fiscal year 1991, eight coordinated

CF carrier screening pilot studies were funded by

NIH at a total of $1,657,086 for the first fiscal year

and $4,442,568 over a 3-year period (80). Six of

these NIH pilots were funded by the National Center

for Human Genome Research’s Ethical, Legal, and

Social Issues (ELSI) program (ch. 2), one by the

National Center for Nursing Research, and one by

the National Institute of Child Health and Human

Development, although all eight are considered a

single consortium (ch. 6). ELSI alone targeted

$1,340,963 in fiscal year 1991 and $3,200,178

through the end of fiscal year 1993 for these pilots

(80).

Private Efforts

The Cystic Fibrosis Foundation is a nonprofit

organization whose mission is to further research,

medical care, public policy, and education for CF. It

dedicates 33 percent of its annual budget to research

towards a cure. CFF maintains research centers at

medical schools and universities throughout the

United States and provides grants to individual

researchers. For calendar years 1991 and 1992, CFF

earmarked $20 million per year for biomedical

research, nearly equivalent to NIH’s extramural

REQUEST FOR APPLICATIONS

New Therapies for th e

Treatment and Cure of

Cystic Fibrosis

Photo credit: Cystic Fibrosis Foundation

Advertisement seeking grant proposals for CF-related

research. The Cystic Fibrosis Foundation funds proposals

that are deemed meritorious by the National Institutes of

Health peer review panels, but that do not receive support

due to lack of funds.
102 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

NIDDK. . . . . . . . . . .

NHLBI. . . . . . . . . . . .

NIAID. . . . . . . . . . . .

NCHGR. . . . . . . . . .

NCRR. . . . . . . . . . .

NICHD. . . . . . . . . . .

NIDR. . . . . . . . . . . .

NEI. . . . . . . . . . . . . .

NIGMS. . . . . . . . . . .

NCNR. . . . . . . . . . .

NIAMS. . . . . . . . . . .

NINDS. . . . . . . . . . .

NIH. . . . . . . . . . . . . .

ADAMHA

NIMH. . . . . . . . . . .

. -

66

12

78

45

9

54

6

3

9

6

3

9

37

3

40

2

1

3

0

4

4

0

2

2

0

3

3

1

0

1

0

1

1

0

1

1

163

43

206

0

1

1

615,300,000

1,126,900,000

907,300,000

87,400,000

335,800,000

479,000,000

148,900,000

253,200,000

760,000,000

39,900,000

193,200,000

541,700,000

8,276,700,000

622,714,000

1.7

0.8

0.2

2.0

0.3

0.1

0.4

0.2

0.04

0.7

0.1

0.03

0.3

0.01

a [nstit~e and Center abbreviations refer, in order, to the following: NIDDK, National Institute of Diabetes and Digestive

and Kidney Diseases; NHLBI, National Heart, Lung, and Blood Institute; NIAID, National Institute of Allergy and

Infectious Diseases; NCHGR, National Center for Human Genome Reseamh; NCRR, National Center for Research

Resourcas; NICHD, National Institute of Child Health and Human Development; NIDR, National Institute of Dental

Research; NEl, National Eye Institute; NIGMS, National Institute of General Medical Sciences; NCNR, National

Center for Nursing Research; NIAMS, National Institute of Arthritis and Musculoskeletal and Sldn Diseases; NINDS,

National Institute of Neurological Disorders and Stroke; NIH, National Institutes of Health; ADAMHA, Alcohol, Drug

Abuse, and Mental Health Administration; NIMH, National Institute of Mental Health.

b CF+elated research is primary fccus of grant.

C CF-related research is secondary focus of gmnt.

d Total CF+elatect research (primary plus =mmclary).

SOURCE: office of Technology Assessment, 1992.
Chapter 4--The State-of-the-Art in Genetics ● 103

funding level (12). Approximately 30 to 40 percent

of the research budget supports studies in gene

therapy, and the balance is spent on research into the

pathophysiological basis of the disease and other

therapies (12). In collaboration with NIH, CFF funds

projects deemed meritorious by the NIH peer review

process but not supported because of lack of funds.

A total of $2 million in calendar year 1991 and $3.6

million in calendar year 1992 has been designated

under this program (12). CFF does not support

research into carrier screening.

HEMI is a philanthropic organization that sponsors biomedical research through support of individual investigators. For fiscal year 1992, $68.9 million, or 34 percent of its research budget, has been

dedicated towards this purpose (16). No breakdown

was available for the amount of spending specifically for CF, but six HHMI investigators who carry

out such research as all or part of their activities

receive a total of $5,743,093 to cover salary,

research materials, and all operative costs (16).

SUMMARY AND CONCLUSIONS

The 1989 isolation of the CF gene-and a single

mutation responsible for about 70 percent of mutations in CF patients and families-opened new

possibilities for understanding the basic defect,

finding a cure, and testing and screening for carriers.

Since then, more than 170 mutations of the CF gene

have been identified. Approximately 13 mutations

account for 85 to 95 percent of CF mutations in the

United States in Caucasians.

One hallmark of CF—its varied symptoms and

severity-sometimes correlates with differences in

genetic mutations. Pancreatic insufficiency, for example, appears to be associated with the most

common mutation (DF508), although other aspects

of the disease have not yet been shown to correspond

to specific mutations.

One outgrowth of identifying the CF gene has

been the ability to directly analyze DNA to detect

carriers of the condition. Although the presence of

multitudinous mutations that vary in frequency

among ethnic and racial groups confounds screening

and DNA diagnosis on clinical, ethical, and legal

levels, new technologies promise to surmount at

least some of the technical difficulties. Coordinating

existing automation and developing new automated

techniques would facilitate rapid, large-scale detection of CF mutations. DNA automation is advancing

at a pace that would enable entirely automated DNA

diagnosis to be realized in the next few years, if this

should be deemed a priority.

Another significant research result has been

elucidation and understanding of the CF gene

product, cystic fibrosis transmembrane conductance

regulator, which could lead to improved diagnosis

and treatment. As research in the underlying mechanism of CF progresses, new molecular-based treatments could further improve the health and quality

of life of affected individuals. Future therapies, for

example, might be targeted at correcting the deficits

in Cl- flow or overcoming the defects in the gene

through gene therapy.

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

CHAPTER 4 REFERENCES

American Society of Human Genetics, Human

Genome Committee Project Report, “The Human

Genome Project: Implications for Human Genetics,” American Journal of Human Genetics L19:687-

691, 1991.

Ames, G.F.-L., Mirnura, C. S., and Shyamala, V.,

“Bacterial Periplasrnic Permeases Belong to a

Family of Transport Proteins Operating From

Escherichia coli to Human: Traffic ATPases,”

FEMS Microbiology Reviews 75:429-226, 1990.

Anderson, M. P., Berger, H. A., Rich, D. P., et al.,

“Nucleoside Triphosphates Are Required to Open

the CFTR Chloride Channel, ” Cell 67:775-784,

1991.

Anderson, M. P., Gregory, R. J., Thompson, S., et al.,

“Demonstration that CFIR Is a Chloride Channel

by Alteration of Its Anion Selectivity, ” Science

253:202-205, 1991.

Anderson, M. P., Rich, D. P., Grego~, R.J., et al.,

‘‘Generation of cAMP-Activated Chloride Currents

by Expression of CFI’R,” Science 251:679-682,

1991.

Anderson, W. F., ‘‘Human Gene Therapy, ” Science

256:808-813, 1992.

Bal, J., Sturhman, M., Schloesser, M., et al., “A

Cystic Fibrosis Patient Homozygous for the Nonsense Mutation R553X, ’ Journal of Medical Genetics 28:715-717, 1991.

Barasch, J., Kiss, B., Prince, A., et al., “Defective

Acidification of Intracellular Organelles in Cystic

Fibrosis,” Nature 352:70-73, 1991.

Barinaga, M., 4 ‘Will ‘DNA Chip’ Speed Genome

Initiative?,” Science 253: 1489, 1991.

Barinaga, M., ‘‘Novel Function Discovered for the

Cystic Fibrosis Gene, ” Science 256:~5, 1992.
104 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

Barreto, C., Pinto, L. M., Duarte, A., et al., “A

Fertile Male With Cystic Fibrosis: Molecular Genetic Analysis, ” Journal of Medical Genetics

28:420421, 1991.

Bean, R., Cystic Fibrosis Foundation, Bethesda,

MD, personal communication, November 1991.

Bear, C. E., Li., C., Kartner, N., et al., ‘‘Purification

and Functional Reconstitution of the Cystic Fibrosis

Transmembrane Conductance Regulator (CITR),”

Cell 68:809-818, 1992.

Beaudet, A. L., Howard Hughes Medical Institute,

Baylor College of Medicine, Houston, TX, personal

communication, February 1992.

Beugelsdijk T. J., Ims Alamos National Laboratory,

Los Alamos, NM, personal communication, 1991.

Blanchard, F., Howard Hughes Medical Institute,

Bethesda, MD, personal communications, November 1991, February 1992.

Boat, T. F., Welsh, M. J., and Beaudet, A.L., “Cystic

Fibrosis,” The Metabolic Basis of Inherited Disease, C.R. Scriver, A.L. Beaudet, W.S. Sly, et al.

(eds.) (New Yorlq NY: McGraw Hill, 1989).

Bobrow, M., Pediatric Research Unit, Division of

Medical and Molecular Genetics, Unittxl Medical

and Dental Schools of Guy’s and St. Thomas’s

Hospital, Imndon, England, personal communication, December 1991.

Bonduelle, M., Lissens, W., Liebaers, I., et al.,

“Mild Cystic Fibrosis in Child Homozygous for

G542 Non-Sense Mutation in CF Gene,” L.uncet

338:189, 1991.

Borgo, G., Mastella, G., Gasparini, P., et al.,

“Pancreatic Function and Gene Deletion F508 in

Cystic Fibrosis,” Journal of Medical Genetics

27:665-669, 1990.

Borrnan, S., “Gene Therapy Eyed to Elicit Cancer

Immunity,’ Chemical and Engineering News 69:6,

1991.

Bradbury, N. A., Jilling, T, Berta, G., et al., “Regulation of Plasma Membrane Recycling by CIWR,”

Science 256:530-532, 1992.

Cantor, C., Southern, E., and Mixzzabekov, A.,

‘‘Moscow Workshop on Sequencing by Hybridization,” Human Genome News 3:12-13,16, 1992.

Caskey, C.T., “Disease Diagnostics by Recombinant DNA Methods, ’ Science 236:1223-1228,

1987.

Chalkley, G., and Harris, A., “A Cystic Fibrosis

Patient Who Is Homozygous for the G85E Mutation

Has Very Mild Disease,” Journai of Medical

Genetics 28:875-877, 1991.

Cheng, S. H., Gregory, R. J., Marshall, J., et al.,

‘ ‘Defective Intracellular Transpofi and Processing

of CITR is the Molecular Basis of Most Cystic

Fibrosis, ” Cell 63:827-834, 1990.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

Cheng, S. H., Rich, D, P,, Marshall, J., et al.,

“Phosphoxylation of the R-Domain by cAMPDependant Protein Kinase Regulates the CFI’R

Chloride Channel,” Cell 66:1027-1036, 1991.

Coghlan, A., “Dyes Could Speed Up the Genome

Project. . .,” New Scientist 133:25, 1992.

Collaborative Research Inc., Wahham, MA, “Now

. . . A Test to Iden@ Greater than 90% of Cystic

Fibrosis Carriers,’ advertisement, 1991.

Collins, F.S., “Cystic Fibrosis: Molecular Biology

and Therapeutic Implications,” Science 256:774-

779, 1992.

Cooper, D.N., and Schmidtke, J., “Diagnosis of

Genetic Disease Using Recombinant DNA. Third

Edition,” Human Genetics 87:519-560, 1991.

Crystal, R.G., National Institutes of Health, Bethesd~ MD, presentation before the U.S. Congress,

Office of Twhnology Assessment, Advisory Panel

on Cystic Fibrosis and DNA Tests: Implications of

Carrier Screening, September 1991.

Cuppens, H., Miuyen, P., De Boec~ C., et al., “A

Child, Homozygous for a Stop Codon in Exon 11,

Shows Milder cystic Fibrosis Symptoms Than Her

Heterozygous Nephew,” Journal of Medical Genetics 27:717-719, 1990.

Cutting, G.R., Curristin, S.M., Nash, E., et al.,

“Analysis of Four Diverse Population Groups

Indicates That a Subset of Cystic Fibrosis Mutations

Occur in Common Among Caucasians,” Arnm”can

Journul of Human Genetics 50:1 185-1194, 1992.

Cutting, G.R., Kasch, L.M., Rosenstein, B.J., et al.,

‘‘A Cluster of Cystic Fibrosis Mutations in the First

Nucl@ide-Binding Fold of the Cystic Fibrosis

Conductance Regulator Protein,” Nature 346:366-

369, 1990.

Cystic Fibrosis Genetic Analysis ConsortiW “Worldwide Survey of the AF508 Mutation-Report from

the Cystic Fibrosis Genetic Analysis Consofiium,’

American Journal of Human Genetics 47:354-359,

1990.

Dalemans, W., Barbry, P., Champigny, G., et al.,

‘‘Altered Chloride Ion Channel Kinetics Associated

With the AF508 Cystic Fibrosis Mutation,” Nature

354:526-528, 1991.

Dean, M., White, M. B., Amos, J., et al., “Multiple

Mutations in Highly Consemed Residues Are

Found in Mildly Affected Cystic Fibrosis Patients,

Cell 61:863-870, 1990.

Drumm, M. L., Pope, H. A., Cliff, W. H., et al.,

“Correction of the Cystic Fibrosis Defect In Vitro

by Retrovirus-Mediated Gene Transfer,” Cell 62:1227-

1233, 1990.

Drumm, M. L., Wilkinson, D. J., Smit, L. S., et al.,

“Chloride Conductance Expressed by AF508 and

Other Mutant CITRS in Xenopus Oocytes, ’ Science 254: 1797-1799, 1991.
Chapter 4-The State-of-the-Art in Genetics ● 105

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

Endo, I., Soeda, E., Murakarni, Y., et al., “Human

Genome Analysis System, ” Nature 352:89-90,

1991.

Erlich, H. A., Gelfand, D,, and Sninsky, J.J., “Recent Advances in the Polymerase Chain Reaction, ’

Science 252:1643-1651, 1991.

Feigner, P. L., and Rhodes, G,, “Gene Therapeutics,” Nature 349:351-352, 1991.

Ferrari, M., Colombo, C., Sebastio, G., et al.,

“Cystic Fibrosis Patients With Liver Disease Are

Not Genetically Distinct,” American Journal of

Human Gerwtics 48:815-816, 1991.

Friedman, K. J,, Highsmith, W. E., and Silverman,

L. M., “Detecting Multiple Cystic Fibrosis Mutations by Polymerase Chain Reaction-Mediated SiteDirected Mutagenesis,’ Clinical Chemistry 37:753-

755, 1991.

Frizzell, R. A., “Cystic Fibrosis: A Disease of Ion

Channels?,” Trends in Neuroscience 10:190-193,

1987.

Frizzell, R. A., and Cliff, W. H., “Back To the

chloride Channel,” Nature 350:277-278, 1991.

Gershon, D., “NIH Merger to Shorten Review,”

Nature 355:664, 1992.

Gibson, A. L., Wagner, L. M., Collins, F, C., et al.,

“A Bacterial System for Investigating Transport

Effects of Cystic Fibrosis-Associated Mutations,”

Science 254:109-1 11, 1991.

Grannell, R., Solera, J., Carrasco, S., et al., “Identification of a Nonframeshift 84-bp Deletion in Exon

13 of the Cystic Fibrosis Gene,’ American Journal

of Human Genetics 50:1022-1026, 1992.

Gray, J,, “Instrumentation Is the Key to Mapping,

Sequencing,’ Human Genome News 3:1-4, September 1991,

Gregory, R. J., Cheng, S.H., Rich, D. P., et al.,

‘‘Expression and Characterization of the Cystic

Fibrosis Transmembrane Conductance Regulator,’

Nature 347:382-386, 1990.

Griffin, R. D., “Gene Therapy, ” Congressional

Quarterly Researcher 1:779-797, 1991.

Haliassos, A., Chomel, F. C., Tesson, L., et al.,

“Modification of Enzymatically Amplified DNA

for the Detection of Point Mutations, ” Nucleic

Acids Research 17:3606, 1989.

Hall, J. G., “Genomic Imprinting and Its Clinical

Implications, ’ New England Journal of Medicine

326:827-829, 1992.

Hammond, K. B., Abman, S. H., Sokol, R. J., et al.,

‘ ‘Efficacy of Statewide Neonatal Screening for

Cystic Fibrosis by Assay of Trypsinogen Concentrations, Ncw EnglandJournal @Mcdicirw 325:769-

774, 1991.

Herman, R., “Gene Therapy Is No Longer a

Rarity, ’ \Vashington Post, Jan. 21, 1992, Health 7.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

Higgins, C. F., “Protein Joins Transpofl Family,”

Nature 341 :103, 1989.

Higgins, C.F., and Hyde, S. C., “Channeling Our

Thoughts, “ Nature 352:194-195, 1991.

Higuchi, R., Dollinger, G., Walsh, P. S., et al.,

“Simultaneous Amplification and Detection of

Specific DNA Sequences, ‘‘ Biotechnology 10:413-

417, 1992.

Holden, C. (cd.), ‘Aerosol Gene Therapy, ’ Science

253:964-965, 1991.

Holden, C. (cd.), “Gene Therapy Trials on the

Move,” Science 254:372, 1991.

Holden, C. (cd.), “Genetics ‘Force de Frappe’,”

Science 251 :623, 1991.

Hunkapiller, T., Kaiser, R.J., Koop, B. F., et al.,

“Large-Scale and Automated DNA Sequence Determination,” Science 254:59-67, 1991.

Hyde, S. C., Emsley, P., Hartshom, M. J., et al.,

‘‘Structural Model of A~-Binding Proteins Associated With Cystic Fibrosis, Multidrug Resistance

and Bacterial Transpofi, ’ Nature 346:362-365,

1990.

Integrated Genetics Laboratones, Inc., Framingham, MA, “CF/12 Mutation Test for Cystic Fibrosis,” brochure, fall 1991.

Jett, J. H., Los Alamos National Laboratory, Los

Alamos, NM, personal communication, September

1991.

Jett, J. H., Keller, R. A., Martin, J. C., et al., “HighSpeed DNA Sequencing: An Approach Based Upon

Fluorescence Detection of Single Molecules, ’ Journal of Bimolecular Structure and Dynamics7:301 -

309, 1989.

Jilling, T., Cunningham, S., Barker, P. B., et al.,

‘‘Genetic Complementation in Cystic Fibrosis Pancreatic Cell Lines by Somatic Cell Fusion, ’ Arnerican Journal ofPhysiology 259: C101O-C1O1 5,1990.

Johnson, J. A., “Human Gene Therapy,” Congressional Research Service Issue Brief, IB901O8, Apr.

1, 1991.

Jones, C.T, McIntosh, I., Keston, M., et al., “Three

Novel Mutations in the Cystic Fibrosis Gene

Detected by Chemical Mismatch Cleavage: Analysis of Wriant Splicing and a Nonsense Mutation, ’

Human Molecular Genetics 1:1 1-17, 1992.

Kartner, N., Hanrahan, J. W., Jensen, T. J., et al.,

‘ ‘Expression of the Cystic Fibrosis Gene in NonEpithelial Cells Produces a Regulated Anion Conductance, ” Cell 64:681-691, 1991.

Kazazian, H. H., Center for Medical Genetics, Johns

Hopkins Hospital, Baltimore, MD, personal communication, December 1991.

Kerem, B.-S., Romrnens, J. M., Buchanan, J. A., et

al., “Identification of the Cystic Fibrosis Gene:

Gene[ic Analysis,’ Science 245:1073 -108O, 1989.
106 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

75,

76.

77<

78,

79,

80.

81.

82.

83.

84.

85,

86.

87.

88.

89.

Kerem, B.-S., Zielenski, J., Markiewicz, D., et al.,

‘ ‘Identification of Mutations in Regions Corresponding to the Two Putative Nucleotide (ATP)-

Binding Folds of the Cystic Fibrosis Gene, ”

Proceedings of the National Academy of Sciences,

USA 87:8447-8451, 1990.

Kerem, E., Corey, M., Kerem, B.-S., et al., ‘‘The

Relation Between Genotype and Phenotype in

Cystic Fibrosis-Analysis of the Most Common

Mutation, ’ New England Journal of Me&”cine

323:1517-1522, 1990.

Knowlton, R. G., Cohen-Haguenauer, O., Van Cong,

N., et al., “A Polymorphic DNA Marker Linked to

Cystic Fibrosis Is Imcated on Chromosome 7,”

Nafure 318:380-382, 1985.

Knstidis, P., Bozon, D., Corey, M., et al., “Genetic

Determination of Exocrine Pancreatic Function in

Cystic Fibrosis,” American Journal of Human

Genetics 50:1 178-1184, 1992.

Landegren, U., Kaiser, R., Caskey, C. T., et al.,

“DNA Diagnostics: Molecular Techniques and

Automation,” Science 242:229-237, 1988.

Langfelder, E. J., National Center for Human

Genome Research, National Institutes of Health,

Bethesda, MD, personal communication, February

1992.

Lm_nna, W. K., Feldman, G. L., Kerem, B.-S., et al.,

‘ ‘Mutation Analysis for Heterozygote Detection

and the Prenatal Diagnosis of Cystic Fibrosis, New

England Journal of Medicine 322:291-296, 1990.

hwis, R,, “Innovative Alternatives to PCR Technology Are Proliferating, ’ The Scientist Jan. 21,

1991, p. 23.

Marrone, B. L., Ims Alamos National Laboratory,

Los Alamos, NM, personal communication, September 1991.

MarWick, C., “Gene Replacement Therapy Enters

Second Year,” Journal of the American Medical

Association 266:2193, 1991.

McBride, G., ‘‘Nontraditional Inheritance+-11: The

Clinical Implications,” Mosaic 22:12-25, 1991.

McCabe, E. R. B., “Genetic Screening for the Next

Decade: Application of Present and New Technologies, ” Yale Journal of Biology and Medicine

64:9-14, 1991.

McCabe, E. R. B,, “Implementation of DNA Technology” Yale Journal of Biology and Medicine

64: 19-20, 1991.

McKusick, V. A., Mendelian Inheritance in Man.

Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes, 9th ed. (Baltimore, MD: The Johns Hopkins University Press,

1990).

Ng, I. S. L., Pace, R., Richard, M. V., et al., ‘‘Methods

for Analysis of Multiple Cystic Fibrosis Mutations, ’ Human Cenelies 87:613-617, 1991.

90.

91.

92.

93.

94.

95,

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

Nickerson, D. A., Kaiser, R., Lappin, S., et al.,

“Automated DNA Diagnostics Using an ELISABased Oligonucleotide Ligation Assay, ’ Proceedings of the National Acaakmy of Sciences, USA

87:8923-8927, 1990.

Nunes, V., Bonizzato, A., Gaona, A., et al., “A

Frameshift Mutation (2869insG) in the Second

Transmembrane Domain of the CIWR Gene: Identification, Regional Distribution, and Clinical Presentation, ’ Amen”can Journal of Human Genetics

50:1 140-1142, 1992.

Osborne, L., Knight, R., Santis, G., et al., “A

Mutation in the Second Nucleotide Binding Fold of

the Cystic Fibrosis Gene, ’ American Journal of

Human Genetics 48:608-612, 1991.

Parham, P., “Transporters of Delight,” Nature

348:674-675, 1990.

Pollard, M., Lawrence Berkeley Laboratory,

Berkeley, CA, personal communication, September

1991.

Quinton, P. M., “Cystic Fibrosis: A Disease in

Electrolyte Transpofi, ” FMEB Journal 4:2709-

2717, 1990.

Quinton, P. M., “Righting the Wrong Protein, ”

Nature 347:226, 1990.

Rich, D. P., Anderson, M. P., Gregory, R.J., et al.,

“Expression of Cystic Fibrosis Transmembrane

Conductance Regulator Corrects Defective CMoride Channel Regulation in Cystic Fibrosis Airway

Epithelial Cells, ” Nature 347:358-363, 1990.

Rich, D. P., Gregory, R.J,, Anderson, M.P., et al.,

“Effect of Deleting the R Domain on CITRGenerated Chloride Channels,” Science 253:205-

207, 1991.

Rigot, J.-M., Lafitte, J.-J., Dumur, V., et al., ‘Cystic

Fibrosis and Congenital Absence of the Ws Deferens,’ New England Journal of Medicine 325:64-65,

1991.

Ringe, D., and Petsko, G. A., “A Transport Problem’?,” Na[ure 346:312-313, 1990.

Riordan, J. R., Rommens, J. M., Kerem, B.-S., et al.,

“Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary DNA, ’

Science 245:1066-1072, 1989.

Roberts, L., “Cystic Fibrosis Corrected in Lab,”

Science 249:1503, 1990.

Roberts, S. S., “Push Buttons and the Genome: The

Role of Automation in DNA Sequencing, ’ Journal

of NIH Research 3:89-92, 1991.

Rogers, J., “Nontraditional Inheritance-I: Mechanisms Mendel Never Knew, ’ Mosaic 22:3-1 1,

1991.

Romeo, G., and Devoto, M. (eds.), “Population

Analysis of the Major Mutation in Cystic Fibrosis, ’

f{urnan Genetics 85:391445, 1990.
Chapter 4--The State-of-the-Art in Genetics ● 107

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116,

117

118

Rommens, J. M., Dho, S., Bear, C. E., et al., “CyclicAMP-Inducible Chloride Conductance in Mouse

Fibroblast Lines Stably Expressing Human Cystic

Fibrosis Transmembrane Conductance Regulator

(CITR),” Proceedings of the National Academy of

Sciences, USA 88:7500-7504, 1991.

Rommens, J. M., Iannuzzi, M. C,, Kerem, B.-S., et

al., ‘‘IdentKlcation of the Cystic Fibrosis Gene:

Chromosome Walking and Jumping,’ Science

245:1059-1065, 1989.

Rosenfeld, M. A., Siegfried, W., Yoshirnura, K., et

al., ‘ ‘Adenovirus-Mediated Transfer of a Recombinant Alpha-1 -Antitrypsin Gene to the Lung Epitheliums In Vivo,” Science 252:431-434, 1991.

Rosenfeld, M. A., Yoshimura, K., Trapnell, B. C., et

al., ‘‘In Vivo Transfer of the Human Cystic Fibrosis

Transmembrane Conductance Regulator Gene to

the Airway Epitheliums, ” Cell 68:143-155, 1992.

Santis, G., Osborne, L., Knight, R. A., et al.,

“Genetic Influences on Pulmonary Severity in

Cystic Fibrosis,” Lancet 334:294, 1990.

Santis, G., Osborne, L., Knight, R. A., et al.,

“Independent Determinants of Pancreatic and Pulmonary Status in Cystic Fibrosis, ” Luncet 336:1081-

1084, 1990.

Santis, G., Osborne, L., Knight, R. A., et al.,

‘‘Linked Marker Haplotypes and the AF508 Mutation in Adults With Mild Pulmonary Disease and

Cystic Fibrosis,” Luncet 335:1426-1429, 1990.

Schloesser, M., Arleth, S., bnz, U,, et al., “A

Cystic Fibrosis Patient With the Nonsense Mutation

G542X and the Splice Site Mutation 171-1,”

Journal of Medical Genetics 28:878-880, 1991.

Shoshani, T., Augarten, A., Gazit, E., et al.,

“Association of a Nonsense Mutation (W1282X),

the Most Common Mutation in the Ashkenazi

Jewish Cystic Fibrosis Patients in Israel, With

Presentation of Severe Disease, American Journal

of Human Genetics 50:222-228, 1992.

Sorscher, E. J., Kirk, K., Weaver, M. L., et al.,

‘‘Antisense Oligodeuxynucleotide to the Cystic

Fibrosis Gene Inhibits Anion Transport in Normal

Cultured Sweat Duct Cells,’ Proceedings of the

National Academy of Sciences, USA 88;7759-7762,

1991.

Strong, TV., Smit, L. S., Tlu_pin, S. V., et al.,

‘ ‘Cystic Fibrosis Gene Mutation in Two Sisters

With Mild Disease and Normal Sweat Electrolyte

Ixwels,’ New’ EnglandJournal cfMedicinc 325: 1630-

1634, 1991.

Swinbanks, D., “The New Automated DNA Sequencer, ’ Nature 351 :593, 1991.

Tabcharani, J. A., Chang, X.-B., and Riordan, J. R.,

‘ ‘Phosphorylation-Regulated Cl- ChanneI in CH O

Cells Stably Expressing the Cystic Fibrosis Gene, ’

Nti[ure 352:628-631, 1991,

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131,

132,

Taylor, C. J., Hughes, H., Hardcastle, P. T., et al.,

“Genotype and Secretory Response in Cystic

Fibrosis,” Luncer 339:67-58, 1992.

Thiel, E., Lawrence Berkeley Laboratory, Berkeley,

CA, personal communication, September 1991.

Thiemann, A., Grunder, S., Pusch, M., et al., “A

Chloride Channel Widely Expressed in Epithelial

and Non-Epithelial Cells, ’ Nature 356:57-

60, 1992.

Thomas, P. J., Shenbagamurthi, P., Ysem, X., et al.,

“Cystic Fibrosis Transmembrane Conductance Regulator: Nucleotide Binding to a Synthetic Peptide, ’

Science 251:555-557, 1991.

Trezise, A. E., and Buchwald, M., “In Vivo CellSpecific Expression of the Cystic Fibrosis Transmembrane Conductance Regulator, ’ Nature 353:434-

427, 1991.

Tsui, L.-C., and Buchwald, M., “Biochemical and

Molecular Genetics of Cystic Fibrosis,” Advances

in Human Genetics, vol. 20, H. Harris and K.

Hirschom (eds.) (New York NY: Plenum Press,

1991).

Tsui, L.-C., Buchwald, M., Barker, D., et al.,

“Cystic Fibrosis Locus Defined by a Genetically

Linked Polymorphic DNA Marker, ” Science 230:

1054-1057, 1985.

Tsui, L.-C., Zengerling, S., Willard, H. F., et al.,

‘‘Mapping of the Cystic Fibrosis hus on Chromosome 7,’ Cold Spring Harbor Symposia on Quantitative Biology 51 :325-335, 1986.

U&r, D., Lawrence Berkeley Laboratory, Berkeley,

CA, personal communication, September 1991.

U.S. Congress, Office of Technology Assessment,

Human Gene Therapy, OTA-BP-BA-32 (Washington, DC: U.S. Government Printing Office, December 1984).

U.S. Congress, Office of T~hnology Assessment,

Techniques for Detecting Heritable Mutations in

Human Beings, OTA-H-298 (Washington, DC:

U.S. Government Printing Office, September 1986).

U.S. Congress, Office of Technology Assessment,

New Developments in Biotechnology: Owrwrship

of Human Tissues and Cells, OTA-BA-337 (Washington, DC: U.S. Government Printing Office,

March 1987).

U.S. Congress, Office of Technology Assessment,

Ne~’ Deteloprnents in Biotechnology>: Public Perceptions of Biotechnology>, OTA-B P- BA-45 (Washington, DC: U.S. Government Printing Office, May

1987).

U.S. Congress, Office of Iixhnology Assessment,

h~apping Our Gene.~-The Genomc Projects: HCWI

Big, How Fast?, OTA-BA-373 (Washington, DC:

U.S. Government Printing Office, April 1988).
108 ● Cystic Fibrosis and DNA Tests: Implications of Carn”er Screening

133.

134.

135.

136.

137.

138.

139.

U.S. Congress, Office of Ttxdmology Assessment,

Genetic Witness: Forensic Uses of DNA Tests,

OTA-BA-438 (Washington, DC: U.S. Government

Printing Office, July 1990).

U.S. Congress, Office of Twhnology Assessment,

Genetic Monitoring and Screening in the

Workplace, OTA-BA455 (Washington, DC: U.S.

Government Printing Office, September 1990).

Mdverde, M. A., Diaz, M., Sepulve@ F. V., et al.,

‘‘Volume-Regulated chloride Channels Associated

With the Human Multidrug-Resistance Pglycoprotein,’ Nature 355:830-833, 1992.

Verm~ I. M., “Gene Therapy,” Scientific American

264:68-84, 1990.

Wainwright, B.J., Scambler, P. J., Schrnidtke, J., et

al., “Immlization of Cystic Fibrosis Imcus to

Human Chromosome 7cenq22,” Nature 318:384-

385, 1985.

Weatherall, D.J., “Gene Therapy in Perspective,”

Nature 349:275-276, 1991.

Weiss, R., “Hot Prospect for New Gene Amplifier,” Science 254:1292-1293, 1991.

140.

141.

142.

143.

144.

145.

146.

147.

Welsh, M. J., “Abnormal Regulation of Ion Channels in Cystic Fibrosis Epithelia,” F~EB Journal

4:2718-2725, 1990.

Welsh, M. J., ‘Acidiflcat.ion Identification,” Nature

352:23-24, 1991.

Welsh, M. J., and Ficlq R. B., “Cystic Fibrosis,”

Journal of Clinical Investigation 80:1523-1526,

1987.

White, R., Woodward, S., hppert, M., et al., “A

Closely Linked Genetic Marker for Cystic Fibrosis,” Nature 318:382-384, 1985.

Wine, J.J., “The Mutant Protein Responds,” Nature 354:503-504, 1991.

Wine, J.J., ‘No CFI’R: Are CF Symptoms Milder?,”

Nature Genetics 1:10, 1992.

Wivel, N., Office of Recombinant DNA Activities,

National Institutes of Health, Bethesda, MD, personal communications, March 1992, June 1992.

Zeitlin, P. I., Crawford, I., Lu, L., et al., “CFTR

Protein Expression in Primary and Cultured Epithelia,” Proceedings of the National Academy of

Sciences, USA 89:344-347, 1992.
Chapter 5

Quality Assurance
Contents

Page

QUALITY ASSURANCE FOR CLINICAL LABOIRATORIES . . . . . . . . . . . . . . . . . . . . . 111

The Clinical Laboratory Improvement Amendments of 1988 . . . . . . . . . . . . . . . . . . . . . . 111

State Authorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

The Role of Professional Societies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

U.S. FOOD AND DRUG ADMINISTRATION AND MEDICAL

DEVICE REGULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

FDA Authority to Regulate Test Kits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Regulatory Future of Cystic Fibrosis Mutation Test Kits . . . . . . . . . . . . . . . . . . . . . . . . . 118

GENETIC SERVICES DELIVERY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Licensing and Certification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Factors Affecting Physician Decisions About Cystic Fibrosis Carrier Screening . . . . 121

Duties of Care for Genetic Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Compensation for Inadequate Genetic Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

CHAPTER 5 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Boxes

5-A. The New York State Genetics Quality Assurance Program . . . . . . . . . . . . . . . . . . . . . 115

5-B. FDA Regulation of In Vitro Diagnostic Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

5-C. Maternal Serum Alpha-Fetoprotein Test Kits and the FDA . . . . . . . . . . . . . . . . . . . . . 119

5-D. Medical Malpractice and Standards of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

5-E. Professional Societies and Standards of Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

5-F. The Maine Medical Liability Demonstration Project: An Alternative

. . . . .

Approach to Set Practice Standards? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Figure

5-1. DNA-Based Test Kit for Cystic Fibrosis Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Chapter 5

Quality Assurance

Quality assurance for cystic fibrosis (CF) carrier

screening is multifaceted. In particular, three aspects

of quality assurance are important to ensuring the

safety, efficacy, and accurate interpretation of DNAbased CF assays:

● the quality of clinical laboratory services;

. the quality of genetic diagnostic kits, reagents,

assays, and instrumentation; and

. the quality of professional services, including

diagnostic and counseling services.

Oversight of quality assurance extends to Federal,

State, and local governments. It includes the judiciW Y, professional societies, and clinical laboratories

as well. All have a stake in ensuring high-quality

diagnostic services, although the extent of involvement varies. For example, all play apart in oversight

of laboratory performance, but the Federal Government has primary responsibility for ensuring the

safety and efficacy of clinical laboratory devices

(e.g., DNA test kits). Professional societies and

courts, on the other hand, have a large impact on the

quality of professional services.

This chapter concentrates on the roles of all

interested parties in ensuring that both private and

public facilities provide high-quality DNA-based

genetic analysis, especially CF mutation screening.

It discusses voluntary versus mandatory standards,

and how both regulatory and nonregulatory mechanisms can facilitate efforts to guarantee high quality.

QUALITY ASSURANCE FOR

CLINICAL LABORATORIES

Laboratories use quality control to ensure that a

laboratory’s results meet predetermined criteria. It

includes the steps taken by a laboratory to produce

valid, reproducible, and reliable results each time the

test is performed. Quality assurance programs document the satisfactory performance of quality control,

and can include proficiency testing and external

inspections (83,84,85). Quality control and quality

assurance are essential components of good laboratory practice.

In 1991, Congress reviewed progress toward

overcoming longstanding difficulties with ensuring

the accuracy of diagnostic laboratory tests performed by facilities across the Nation. Congressional concern persists that quality problems could

remain unresolved, despite recent changes in Federal law (167). Questions about laboratory quality

are important to CF mutation analysis.

First, the quality of a laboratory’s performance

affects the quality of counseling services. Accurate

reporting and interpretation of the mutations used by

a laboratory are necessary if used by genetics and

other health professionals are to convey accurate

results to their clients. Failure to assay a less

common mutation (or to properly interpret the

results of the battery of mutations used) could result

in clients mistakenly believing themselves to be at

negligible risk of conceiving a child with CF.

Conversely, misinterpreting test results could also

mislead individuals to think they are at increased

risk and to decide against conception. Second, the

technical skills of both the technician and laboratory

are essential for maintaining an acceptable standard

of practice to allow a laboratory to conduct DNA

analysis of CF mutations. Today’s assays, for

example, use the polymerase chain reaction (PCR),

and some observers have concerns about the proper

controls to ensure against potential mishaps—

chiefly contamination—using PCR-based techniques

(54,74,169).

Because the intensity of Federal interest in

clinical laboratory performance is new and evolving,

and because Congress has expressly involved itself

by taking action in this area, this section focuses on

recent congressional action, chiefly the Clinical

Laboratory Improvement Amendments of 1988

(CLIA) (Public Law 100-578). States and professional organizations, however, also play key roles in

certain aspects of laboratory quality assurance.

Thus, this section also examines how each has been

involved in specific debates surrounding quality

assurance for clinical facilities performing DNAbased diagnostic procedures, which include carrier

screening and testing for CF.

The Clinical Laboratory Improvement

Amendments of 1988

To remedy problems of inadequate and inconsistent clinical diagnostic testing, the 100th Con-

–11l–
112 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Photo credit: L4vigen, Inc.

Facilities that perform DNA-based diagnostic tests are subject to the Clinical Laboratory Improvements Amendments of 1988.

gress passed legislation that subjects most clinical

laboratories to a number of requirements, including

qualifications for the laboratory director, standards

for the supervision of laboratory testing, qualifications for technical personnel, management requirements, and an acceptable quality control program.

Many of these same standards were already in place

prior to 1988 with regard to laboratories doing

testing for Medicare or accepting samples across

State lines, but CLIA represents the congressional

response to national concern over shortcomings in

the stringency and coverage of the original 1967 law.

Designed to strengthen Federal oversight of laboratories to ensure that test results are accurate and

reliable, CLIA creates a national, unified mechanism

that regulates virtually every laboratory in the

country-not just those involved in interstate commerce or participating in Medicare. Another impact

of CLIA, beyond its extension to all laboratories, is

the integration of the previously separate inspection

and enforcement systems.

Prior to enactment of CLLA, Federal regulations

covered the approximately 12,000 laboratories that

either transported samples between States or performed tests billed to Medicare. In 1990, however,

the Health Care Financing Administration (HCFA)

of the U.S. Department of Health and Human

Services (DHHS) began exercising sweeping regulatory authority over clinical laboratories. HCFA’s

mandate is to set standards for staffing and maintaining all medical laboratories, including physician

office testing. HCFA is also directed to manage a

comprehensive program to police the facilities, and

it can impose sanctions.

Under CLIA, the Secretary of DHHS (hereinafter

the Secretary) shall establish national standards for

quality assurance in clinical laboratory services. The

Secretary must implement recordkeeping, inspection, and proficiency testing programs, and report to

Congress on a range of issues gauging the impact of

various quality assurance mechanisms. Regulatory

requirements will vary according to whether the

facility performs tests considered “simple,” “moderately complex,’ or “highly complex” (42 CFR

493). For example, cytogenetic testing-examining

chromosome profiles—is likely to be considered

“highly complex” (108). DNA-based genetic tests

are not yet covered by the cytogenetics category, but

unless specifically categorized, a test is considered

“highly complex” (57 FR 7245). Tests similar to

DNA-based genetic assays—i.e., DNA analysis to

detect viruses-have been classified “highly complex” (57 FR 7288).

CLIA and the Omnibus Budget Reconciliation

Act of 1989 (Public Law 101-239) grant HCFA the

power to suspend or revoke a lab’s certificate for

violation of the rules. Further, fines up to $10,000 for
Chapter 5-Quality Assurance . 113

each violation or each day of noncompliance can be

levied, and jail sentences of 3 years can be imposed,

The law continues to permit, subject to approval by

the Secretary, States or private associations to

substitute for the Federal accreditation process.

Currently, these include at least the College of

American Pathologists (CAP), the American Association of Bioanalysts, accrediting agencies in three

States, the Joint Commission on Accreditation of

Healthcare Organizations, and the American Osteopathic Association.

Monitoring Laboratory Performance

HCFA will continue using State agencies for

onsite monitoring because those agencies have the

most experience in inspection activities, have the

ongoing responsibilities for assessing laboratory

compliance, inspect an entire facility (HCFA agents

inspect only specific areas), and make periodic

recertification (56 FR 13430).

Beyond onsite monitoring and inspection, proposed HCFA regulations aim to help physicians and

patients avoid laboratories that perform poorly by

issuing an annual laboratory registry (42 CFR

493.1850). The registry will include, for example,

those facilities that have had their CLIA certificates

suspended and those that have had their accreditation withdrawn or revoked. The registry is designed

to create a national enforcement mechanism that

affects virtually every clinical laboratory in the

country.

For the first time, CLIA regulates the estimated

98,000 physician office laboratories. In total, HCFA

estimates that from 300,000 to 600,000 physician,

hospital, and freestanding laboratories in the Nation

could potentially come under these provisions, and

that the registry will likely change the practice

patterns of laboratories across the country. Some

laboratories might close because they cannot meet

the requirements. Others, out of fear of being

sanctioned, might choose not to perform certain

tests. Some laboratories will increase their fees to

private patients to cover the costs of upgrading

facilities to meet CLIA standards and to pay the user

fee (57 FR 7188) being imposed to fund the survey

and other CLIA requirements. Some laboratories,

however, are exempt, including certain State facilities and some performing drug abuse tests (57 FR

7190). Facilities limited to some types of insurance

testing could also be exempt (108).

State Authority Under CLIA

States will be substantially affected by CLIA. On

one level, they will probably experience some

additional administrative burden if they identify an

increased number of noncompliant laboratories. The

principal impact, however, will be on the relationship between the Federal Government and the States

in the area of direct laboratory regulation. Prior to

CLIA’s enactment, the Federal Government had no

regulatory authority over the numerous intrastate

laboratories, including those located in physicians’

offices. These were, in many cases, though not all,

regulated by the States; such facilities are now

subject to CLIA requirements.

As mentioned earlier, however, CLIA does not

preclude continued State regulation and licensure

(57 FR 7188), although the thrust of States’ role is

changed. Primary emphasis focuses on licensing

personnel and providing information, inspection,

and some proficiency testing services. (A later

section in this chapter describes specific State

initiatives in overseeing clinical laboratories.)

Proficiency Testing

One issue of critical concern to Congress in

passing CLIA was proficiency testing programs.

Until CLIA, such programs varied broadly in testing

criteria and in grading of test results. Moreover,

uniform or minimally acceptable Federal standards

did not exist. Now, except under certain circumstances, proficiency testing shall be conducted every

4 months, with uniform criteria for all examinations

and procedures. The Secretary shall also establish a

system for grading proficiency testing performance.

HCFA expects to propose rules on proficiency

testing before the end of 1992. None of these rules

is expected to apply to DNA-based CF tests (65,185).

Sanctions

HCFA has moved more quickly on the issue of

sanctions against laboratories not meeting Federal

requirements (57 FR 7218). Such sanctions can be

imposed instead of, or before, suspending, limiting,

or revoking the laboratory’s certificate and canceling the laboratory’s approval to receive Medicare

payment for its services.

Prior to CLIA and the Omnibus Budget Reconciliation Act of 1987, the only recourse HCFA had

against a noncomplying laboratory was cancellation

of its approval to receive Medicare payment for its
114 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

services. In developing a range of new sanctions,

HCFA has attempted to establish consistency between the enforcement approach for Medicare laboratories and for laboratories that do not participate in

Medicare. At the direction of Congress, the sanctions include directed plans of correction, civil

money penalties, payment for the costs of onsite

monitoring by the agency responsible for conducting certification inspections, and suspension of all or

part of Federal payments to which the laboratory

would otherwise be entitled for services furnished

after the effective date of sanction.

HCFA proposes three levels of noncompliance,

with graduated severity according to levels o f

deficiencies: those posing immediate jeopardy to

patients, those not posing immediate jeopardy, and

those that are minor. HCFA can also impose

sanctions in specific categories or subcategories, and

thus discourage laboratories from performing tests

in which they do not comply with CLIA without

discouraging testing in categories in which no

deficiencies are identified. CLIA also provides for

incarceration and fines for any person convicted of

intentionally violating any CLIA requirement. It

specifies administrative and judicial review procedures available to a laboratory when HCFA imposes

a sanction or suspends, revokes, or limits the

facility’s CLIA certificate.

Impact of CLIA on DNA Tests

As with other clinical diagnostic tests, CLIA will

affect DNA analysis performed by clinical facilities.

Currently HCFA can limit CLIA certificates at the

specialty or subspecialty level. No special category

exists for DNA tests, but facilities performing such

assays clearly fall within CLIA’s regulatory rubric.

Furthermore, HCFA theoretically could limit CLIA

certificates at the level of individual tests rather than

at the specialty or subspecialty level. For example,

a laboratory could lose its authority to perform CF

mutation analyses, while retaining authority to

continue performing, and receiving payment for,

sickle cell tests. Such detailed oversight, however,

would probably strain HCFA’s administrative capacities (34).

One aspect of CLIA important to carrier testing

and screening for CF will be the development of

proficiency testing standards. The legislation is

quite detailed in addressing proficiency testing for

other clinical tests, but is silent for DNA analyses.

Nonetheless, HCFA expects voluntary participation

of DNA laboratories in a proficiency testing program (148). As described later, professional societies and nonprofit associations are likely to play the

major role in this aspect of quality assurance,

although their involvement is neither required nor

approved by HCFA.

State Authorities

Since CLIA, the principal State role in quality

assurance for clinical facilities is licensure and

certification of personnel. All licensing of medical

and clinical personnel is based on State law. State

and Federal tort actions to remedy issues related to

personnel and service quality are discussed separately in this chapter.

As mentioned earlier, however, CLIA does not

prevent States from regulating and licensing facilities within certain guidelines (55 FR 33936). At least

one State views CLIA as too broad-based to

appropriately address issues raised by DNA tests,

California established an expert advisory committee

to develop standards and to hire qualified consultants to conduct onsite inspections. After a pilot study

using voluntary approvals, the California Department of Health Services (CDHS) intends to ask for

specific licensing laws and regulations for DNA and

cytogenetic laboratories. CDHS will use any acceptable national proficiency testing program, but will

develop its own if those being developed by

professional organizations (described in a following

section) are not satisfactory (34).

Another State, New York, has regulated clinical

laboratories since 1964, prior to enactment of the

original Federal legislation in 1967 (184), More

important to the issue of quality assurance for CF

carrier screening, New York State has established a

genetics quality assurance program that includes

requirements for licensing personnel, licensing facilities, laboratory performance standards, and DNAbased proficiency testing (box 5-A).

The Role of Professional Societies

While CLIA clearly expanded the Federal role in

clinical laboratory oversight, the law continues to

permit, subject to approval by the Secretary, the

involvement of other parties in regulating laboratory

practices. In particular, private nonprofit associations and professional societies could have the

greatest impact in proficiency testing. Of those

associations with standing under the past Federal
Chapter 5---Quality Assurance . 115

Box 5-A—The New York State Genetics Quality Assurance Program

Responding to the development of DNA-based tests for genetic conditions, New York State has created a

permit category for genetic tests. Since January 1, 1991, all facilities within the State, or that handle samples from

the State, have had to be State licensed. Included among the types of technologies for which a permit is required

is DNA analysis for carrier or disease status. To date, 40 facilities—15 within New York and 25 out-of-State-have

been accredited.

In the area of personnel qualifications, the New York State regulations detail specific minimum requirements

for training and education of the laboratory director, including experience with molecular biology and genetic

linkage analysis. To receive a laboratory license, applying facilities must undergo an onsite inspection by the New

York State Department of Health, The laboratory also must meet several other requirements, including documenting

that it: periodically tests equipment; monitors and performs proper quality control of its reagents and standards;

adheres to appropriate confidentiality of records; participates in some form of external quality assurance program

(where available); and demonstrates that it has a clear, appropriate, interpretive report format that explains findings

for nongeneticist physicians. These reports must also caution the provider about possible inaccuracies and suggest

alternative or additional testing if necessary. Finally, to maintain its license, the facility must undergo

interlaboratory proficiency testing for DNA analytical methods.

Beginning in August 1992, New York State will administer a quarterly proficiency testing program. Under the

program, a single sample will be sent to accredited laboratories. Using five systems of their choosing, the

laboratories will analyze and interpret results for the unknown sample and report the findings to the State

Department of Health, Clinical Laboratory Evaluation Unit.

SOURCE: Office of Techology Assessment, 1992, based on P.D. Murphy, “New York State Genetics Quality Assurance program,’ meeting

abstract Biotechnology and the Diagnosis of Genetic Disease: Forum on the Technical, Regulatory, and Societal Issues, Arlington

VA, Apr. 18-20, 1991.

regulatory structure, CAP is likely to be most its planned second survey into a national test, to be

important to quality assurance of laboratories doing

DNA analysis.

In 1989, CAP established the Molecular Pathology Resource Committee to develop appropriate

guidelines for all clinical tests involving DNA

probes or other molecular biological techniques. Its

scope includes not only DNA genetic diagnostics,

but also the use of DNA assays to detect infectious

diseases and neoplasms, and for forensic identification. The Committee has administered two DNAbased proficiency testing pilot programs, although

their focus was not genetic disorders (66).

Besides CAP, several organizations are poised to

facilitate the development of monitoring laboratories through proficiency testing for DNA-based

assays. The Council of Regional Networks for

Genetic Services (CORN), which receives Federal

support, has been active in an array of quality

assurance issues for genetic service facilities, including proficiency testing since 1985 (38). The

CORN Proficiency Testing Committee sponsored a

DNA-based genetic test pilot of 20 laboratories in

1990. The Southeastern region has a regional

proficiency testing program, and will be enlarging

completed in 1992; this effort includes CF mutation

analysis (100).

The American Society of Human Genetics (ASHG)

has recently become active in the area. A joint

ASHG/CAP DNA pilot proficiency testing program

commenced in 1992. Full proficiency testing is

planned by 1994 (5,66,99). ASHG and CORN also

have designated liaisons with each other’s efforts.

Proficiency testing is widely viewed as an important component of quality assurance. It provides a

reliable and identifiable benchmark to assess quality

performance; in the past, professional societies’

involvements have predominated. Today, each of

three principal organizations clearly fills a niche in

the evolving area of proficiency testing programs for

genetic DNA assays: Historically, CAP has led and

administered an array of proficiency testing programs; CORN, with its extensive regional structure

and practitioner community emphasis, has long been

active in improving education, training, and laboratory quality to improve genetic services delivery;

and ASHG has served as the leading national

professional society for genetics researchers and

service providers. Cooperation among these groups
116 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

will be essential for the timely development of

proficiency testing programs for DNA-based genetic

diagnostics. Such cooperation will become increasingly important, since professional programs could

affect proficiency testing for CF mutations (and

other DNA tests) well before HCFA proposes

proficiency testing rules under CLIA (100).

U.S. FOOD AND DRUG

ADMINISTRATION AND

MEDICAL DEVICE REGULATION

Today, DNA-based CF tests are done at research

laboratories, commercial facilities, public health

laboratories, and hospitals. Most attention on ensuring high quality focuses on the institution or

individual performing the assay, At some future

date, however, DNA-based genetic tests-e. g., for

CF mutation analysis—will be marketed widely in

the form of kits such as those that exist for pregnancy

testing, infectious disease analysis, or forensic DNA

identification. At least one U.S. company has begun

evaluating a prototype CF mutation test kit in pilot

studies (47,48). Cellmark Diagnostics, U. K., is also

testing a kit that detects DF508 plus three additional

mutations (figure 5-1; ch. 10),

The U.S. Food and Drug Administration (FDA)

has authority to ensure the safety and efficacy of

diagnostic test kits. ’ This section briefly analyzes

FDA approval procedures that might apply to new

genetic diagnostic kits. A comprehensive analysis of

Federal policies and the medical devices industry

appears in a 1984 OTA report (168).

FDA Authority to Regulate Test Kits

FDA regulates drugs, devices, and biologics

during all phases of their development, testing,

production, distribution, and use, Genetic diagnostic

kits fall within the definition of a device—i.e., a

medical device is a health care product that does not

achieve its primary, intended purposes through

chemical action in or on the body, or by being

metabolized. Thus, the extent to which physicians,

genetic counselors, and their clients come to rely on

CF mutation analysis kits--or other DNA-based

genetic test kits—will depend on FDA regulation of

devices.

Figure 5-l—DNA-Based Test Kit for

Cystic Fibrosis Mutations

SOURCE: Cellmark Diagnostics (Imperial Chemical Industries PLC), United

Kingdom, 1992.

FDA’s regulatory options range from registering

an item’s presence and periodically inspecting

facilities to ensure good manufacturing practices, to

setting performance and labeling requirements, to

premarket review of a device. In addition, the agency

may engage in postmarketing surveillance to identify ineffective or dangerous devices; it may ban

devices it deems unacceptable.

The Federal Food, Drug, and Cosmetic Act

of 1938

Products such as in vitro DNA diagnostics are

regulated under section 351 of the Public Health

Service Act (42 U.S.C. 262), but are also subject to

the adulteration, misbranding, and registration provisions of the Federal Food, Drug, and Cosmetic Act

of 1938 (FFDCA) (21 U.S.C. 301 et seq.). Additionally, ‘‘good manufacturing practices” are currently

applied to licensed in vitro diagnostics.

The Medical Device Amendments of 1976 and

Safe Medical Devices Act of 1990

The Medical Device Amendments of 1976 (MDA)

(Public Law 94-295) and the Safe Medical Devices

Act of 1990 (SMDA) (Public Law 101-629) clarfied

and enlarged the 1938 FFDCA definition of ‘‘device’ to include items used in diagnosing conditions

other than disease (e.g., pregnancy, in vitro diagnostic products), and specific products previously

1 ~ough FDA ~]~o could ~ve re@ated rmgents Cwenfly used in CF mutation WJSayS, it does not md likely will not. FDA does not regtdate

reagents unless they are submitted by manufacturers for clearance or approval. Manufacturers of reagents offer them labeled “for investigational use

only. Facilities may develop such reagents into analytical procedures, and then offer tests such as CF mutation analysis-and other DNA-based genetic

diagnostics-as clinical services. The practices, but not reagents, are regulated under CLIA.
Chapter S--Quality Assurance . 117

Box 5-B—FDA Regulation of In Vitro Diagnostic Devices

Under section 5 IO(k) of the Federal Food, Drug, and Cosmetic Act of 1938, manufacturers must notify the U.S.

Food and Drug Administration (FDA) 90 days prior to marketing any medical device thought to be substantially

equivalent to one legally on the U.S. market. On the basis of this submission, FDA evaluates how similar the new

device is to the existing device. (Devices manufactured before passage of the Medical Device Amendments of 1976

(Public Law 94-295) may be exempt from certain regulatory controls.) If FDA finds the proposed device is

substantially equivalent, FDA notifies the manufacturer that it can be marketed. Since 1976, 6 percent of new

devices underwent stringent premarket review (clinical trials and other demonstrations of safety and effectiveness);

94 percent were reviewed and entered the market on data provided by manufacturers that indicated they were

substantially equivalent to existing devices (162).

At present, the majority of biotechnology-based medical devices represent clinical laboratory or in vitro

diagnostic applications. In vitro diagnostic devices include reagents, instruments, and systems intended for use in

the diagnosis of disease or other conditions-including a determination of the state of health-in order to cure,

mitigate, treat, or prevent disease or its sequelae. Manufacturers submit about 1,200 new in vitro diagnostic

applications each year to FDA, of which a significant percentage are biotechnology-based.

Although most biotechnology in vitro diagnostic devices submitted are monoclinal antibody-based reagent

systems, a number employ DNA technologies, particularly those that detect and identify infectious agents in clinical

specimens. The majority of these applications are processed through FDA’s 5 IO(k) premarket notification program.

Under the 510(k) process, a proposed device maybe marketed if it is demonstrated to be substantially equivalent

to a legally marketed U.S. product, In many cases, a biotechnology-based in vitro diagnostic device can be shown

to be equivalent if the sponsor demonstrates that the new item has essentially equivalent intended use, performance

characteristics, and patient risk to an existing product. For example, the first DNA tests for infectious agents were

compared to previously cleared 510(k) monoclinal antibody reagents for the same intended uses.

In some instances, comparison to an existing conventional product is not possible and, therefore, introduction

raises new types of risk questions that require scientific evaluation of safety and effectiveness through the premarket

approval process. In this case, the new product would be classified as Class III, and subject to the regulatory scheme

described elsewhere in this chapter. Such was the case for the review of a DNA test for gene rearrangements to assess

certain leukemias.

With enactment of the Safe Medical Devices Act of 1990 (Public Law 101-629), manufacturers now

introducing a permanently implantable device, a life supporting or life sustaining device, or a device that potentially

presents a serious risk to health must conduct postmarked surveillance of the device. FDA may also require any other

manufacturer of a device, such as a CF mutation test kit, to conduct postmarked surveillance.

SOURCE: Office of Technology Assessment, 1992, based on K.B Hellman and J.L Hackett, U.S. Food and Drug Administ ration, Rockville,

MD, personal communication December 1991.

regulated as new drugs (e.g., bone cement, sutures, dressed. SMDA expands FDA authority to require

or soft contact lenses). Based on the 1976 amendments, DNA-based genetic tests would be considered “devices.’ Box 5-B describes the general

regulatory process FDA employs for in vitro diagnostic devices, similar to those under development

for CF mutations.

FDA formed the Center for Devices and Radiological Health in 1982 to centralize both the

implementation of MDA (and now SMDA) and the

development of programs to ensure that unsafe and

ineffective medical devices are not sold in the

United States. With SMDA, Congress intended that

perceived shortcomings in MDA would be adpostmarketing surveillance and to order a temporary

or permanent halt to sales of a device in light of

postmarketing surveillance results. (FDA’s new

authority was demonstrated in early 1992 with its

consideration of silicone breast implants (73).)

SMDA also expands the category of facilities and

users required to communicate problems to FDA.

MDA/SMDA directs FDA to classfiy devices into

one of three categories, with different levels of

regulation applying to each.

Class I Devices. Class I contains devices for

which general controls authorized by MDA/SMDA

are sufficient to provide a reasonable assurance of
118 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

safety and effectiveness. Before they can be marketed in the United States, new Class I devices that

have not been exempted require premarket notification to FDA demonstrating their substantial equivalence to legally marketed devices. Manufacturers of

Class I devices are subject to general controls,

meaning they must register their establishments, List

the devices with FDA, conform to good manufacturing practices, and submit to periodic inspections (21

U.S.C. 360).

Theoretically, genetic test kits could fall within

this frost of three classifications. Included in Class I

are: chlarnydia serological reagents, dye and chemical solution stains, tissue processing equipment,

blood bank supplies, and examination gowns. One

current Class I product used for genetic diagnosis is

the chromosome culture kit, defined as “a device

containing the necessary ingredients . . . used to

culture tissues for diagnosis of congenital chromosomal abnormalities” (21 CFR 864.2260).

Class II Devices. Class II is a regulatory class of

devices for which general controls are insufficient to

provide a reasonable assurance of safety and effectiveness and for which scientific information is

sufficient to establish ‘‘special controls’ to provide

such assurances. The’ general control provisions of

Class I devices also apply to Class II devices, as does

the premarket notification requirement. In addition,

Class II devices must meet special controls, which

can include adherence to performance standards,

postmarketing surveillance, establishment of patient

registries, and clinical data submission. Older,

established genetic test kits not involving DNA

methods (e.g., abnormal hemoglobins and alpha-lantitrypsin assays) have been designated as Class II

(21 CFR 862,864, 868).

In theory, DNA-based genetic diagnostic kits

could be classified at this level if FDA determined

that general controls, such as good manufacturing

practices, are insufficient to give the kits the

reliability already exhibited by similar kits classified

in Class I. If, for example, FDA considered a

DNA-based CF mutation analysis kit similar to

abnormal hemoglobin assays, it might classify it as

Class II. On the other hand, if FDA finds the

reliability of the technologies used in DNA-based

diagnostic tests differs substantially, or if the tests

raise new issues of safety and effectiveness, FDA

could define it as Class III. In fact, concern about the

reliability of a DNA-based kit that employs essentially the same methods-PCR and DNA probes—

as those that might be developed for CF tests has

been raised in criminal court (74).

Class III Devices. Devices purported to be “life

supporting, life sustaining, or for a use which is of

substantial importance in preventing impairment of

human health,” or “devices which present an

unreasonable risk of illness or injury” comprise

Class III. In addition to general controls, these

products require premarket approval by FDA based

on data demonstrating that a device is safe and

effective for its intended use. Manufacturers introducing Class III devices since January 1991 have

been required to conduct postmarked surveillance.

(SMDA additionally empowered FDA to require

any other manufacturer of an existing device to

conduct postmarked surveillance.)

Examples of Class III devices include a DNA

probe to detect the “Philadelphia chromosome” in

patients with myelogenous leukemia, tests to detect

chromosomal rearrangements in certain immune

cells, and maternal serum alpha-fetoprotein (MSAFP)

assays for neural tube defects. Class III is an

automatic classification level for new devices not

yet shown to be substantially equivalent to an

existing device on the market-about 2 percent per

year. About 5 percent of all medical testing devices

are ultimately subject to Class III regulation (51 FR

26342), and it is likely that DNA-based test kits will

be categorized as Class III (185,189,190).

Investigational Device Exemption. Under the

Investigational Device Exemption, FDA may exempt investigational devices from regulatory requirements that might hinder developing scientific

data demonstrating safety and effectiveness. In most

cases, these clinical studies of medical devices are

performed to gather data or to support a premarket

notification submission or a premarketing approval

application.

Regulatory Future of Cystic Fibrosis

Mutation Test Kits

Experience with other test kits, such as that for

MSAFP (box 5-C), could shed light on the regulatory future of CF mutation test kits. On the other

hand, congressional concerns about medical device

regulation and SMDA have occurred since the

debate about MSAFP test kits (152-160,164-

166,168), although questions persist about the adequacy of medical device regulation (163). Further,
Chapter 5---Quality Assurance ● 119

Box 5-C—Maternal Serum Alpha-Fetoprotein Test Kits and the FDA

In many respects, questions raised in the 1970s and 1980s about screening the serum of pregnant women to

determine the concentration of alpha-fetoprotein parallel today’s debate about routine carrier screening for cystic

fibrosis (CF). (See also ch. 6.) One controversy surrounding maternal serum alpha-fetoprotein (MSAFP) screening

involved FDA approval of test kits.

In the 1970s, British medicine had taken the lead in assessing MSAFP screening to detect neural tube defects.

Based on a study of 5,800 patients screened for MSAFP in the United Kingdom, the Immunological Panel of the

Bureau of Medical Devices, U.S. Food and Drug Administration (FDA), recommended in June 1977 that MSAFP

test kits be classified as Class 11 devices. The panel further recommended that FDA require kits be labeled to indicate

that a single positive test did not constitute an accurate diagnosis in and of itself and was insufficient to warrant

pregnancy termination, although some panel members (and outside experts) viewed this recommendation as an

overextension of FDA authority and an inappropriate attempt to regulate medical practice.

Historically, reagents used in MSAFP screening either qualified under the Investigational Device Exemption

(IDE) (21 CFR, part 812) or were not directly regulated because the components were produced within a laboratory

for its own diagnostic use. MSAFP test kits, however, were not commercially marketed in the United States prior

to the enactment of the Medical Device Amendments of 1976 (MDA) (Public Law 94-295), and thus were subject

to MDA. In October 1978, FDA appeared to be on the verge of releasing MSAFP test kits on an unrestricted basis.

Concern about the kits quickly mounted from laboratories, physicians, consumers, and professional societies

such as the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics. As with

CF carrier screening, objections about the accuracy of the test, the difficulty in interpreting results, and the potential

burden from increased caseloads for genetic counselors were raised. Concern was also voiced that anti-abortion

groups were influencing FDA to slow approval. Others complained, by contrast, that commercial influences were

rushing the move to approve MSAFP kits, which had 1979 sales of $250 million outside the United States. Some

contended that FDA’s decision to send the device to the Immunological Advisory Group (rather than to a panel of

obstetricians and geneticists) resulted in inadequate attention to some of the clinical and programmatic aspects of

widespread use of the kits (34).

In February 1979, FDA held a public hearing on MSAFP test kits before two of its advisory committees (the

Obstetrics-Gynecologic Device Section and the Immunology Device Section); in August 1979, FDA announced it

intended to restrict the sale, distribution, and use of MSAFP test kits. FDA classified MSAFP test kits as Class III,

which required premarket approval. Further, premarketing approval applications (PMAs) would not be approved

until FDA determnined what restrictions, if any, were necessary to ensure the reliability, safety, and efficacy of the

kits, Manufacturers were not permitted to distribute MSAFP kits in the United States for investigational use under

the IDE. In November 1980, FDA published 13 proposed restrictions for MSAFP test kits (45 FR 74158), and

announced public comment would be received at hearings in January 1981.

Despite support for the restrictions—based on concerns about accuracy and efficacy as just described-several

objections were raised to FDA’s proposed rules. Testimony was offered that 90 percent of hospitals offered MSAFP

screening and were using materials not regulated (because they were not kits); that FDA’s lack of action on pending

PMAs violated due process under MDA; that the proposed regulations extended beyond medical device regulation

under MDA into the realm of clinical laboratory regulation (generally the domain of the Health Care Financing

Administration and the Centers for Disease Control); and that the proposed regulations thrust FDA into an

inappropriate role of regulating private medical practice.

FDA issued revised regulations in 1983, and MSAFP test kits have been widely employed in the United States

since that time. Today, the debate is less a matter of the approval of the test kit per se, but on ancillary issues that

include the role of State health agencies (35) and whether results generated by small, decentralized laboratories are

of lower quality (98, 144).

SOURCE: Office of Technology Assessment, 1992.

because each device is evaluated on a case-by-case The 1984 medical devices reporting (MDR)

basis, the regulatory future of a PCR-based CF (or regulation and SMDA require a report to FDA of any

comparable) test kit remains speculative until one association between a device and serious injury or

wends its way through the FDA process. death of a patient and could be one level of quality
120 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

assurance of CF test kits. The regulation, however,

is limited to instances of patient death or serious

injury. Because use of test kits like those under

development for CF is unlikely to result in injury or

death to a patient, problems are not likely to be

reported on this basis. Kits with poor reliability

could, however, lead to unnecessary pregnancy

terminations, as well as cause significant emotional

harm to patients. The prospect of such pregnancy

terminations might prompt FDA to order postmarketing surveillance of CF test kits.

If the MDR regulation and SMDA were to apply

to genetic diagnostic kits, they might serve as an

early warning system of problems with accuracy and

reliability. The congressional General Accounting

Office (GAO) found that the MDR regulation

generally increased the flow of information about

device defects by a factor of 7. Nonetheless, GAO

estimated that, prior to SMDA, only one-fourth of

manufacturers were in compliance and that FDA

was ill-equipped to handle the data flow, data

management, and data analysis required (161,162).

In the absence of an actual product, what is the

regulatory outlook for test kits like those under

development for CF carrier screening? Enhanced

postmarketing surveillance under SMDA, coupled

with a shift within FDA toward increased regulatory

attention to medical devices, might indicate CF

mutation analysis kits will be subject to more

stringent review than previous non-DNA genetic

test kits. FDA recently embarked on a series of

measures directed at tightening up regulation and

postmarketing surveillance of devices, as well as

other items regulated by FDA (73,78). One target of

increased regulatory attention, for example, has been

monoclinal antibody kits, which are being subjected

to increased scrutiny (53). The general change in

tone at FDA and accompanying personnel changes

have led to consternation among some industry

spokespersons (81). Thus, it is difficult to predict

how MDA and SMDA will ultimately apply to

DNA-based diagnostic test kits.

GENETIC SERVICES DELIVERY

Delivering high-quality genetic services to clients

depends on ensuring a su.fflcient number of skilled

professionals, which in turn demands adequate

education and training. Developing and ensuring

that high standards are maintained, providing mechanisms to evaluate professional performance, and

affording methods for client redress when lapses

occur are the subjects of the following section of this

chapter. In particular, this section addresses:

●

●

●

whether primary care physicians (e.g., obstetricians/gynecologists, internists, or family practice specialists) are now expected to discuss CF

mutation tests or to provide genetic services

related to them as an aspect of routine medical

care;

what all genetic professionals-physicians, genetic counselors, nurses, social workers, or

Ph.D. clinical geneticists—are expected to do

when counseling individuals about the assays;

and

what remedies exist for consumers harmed by

inadequate care.

Licensing and Certification

For genetic tests and information-as for other

medical procedures-the quality of care is largely

determined by the expertise of the health professionals and the quality of the laboratory services. The

expertise and reliability of the providers, in turn,

depends on the quality of medical and genetics

education (ch. 6) and the quality of State certification, licensure, and discipline of such professionals

within its jurisdiction.

Genetics professionals who are physicians are

formally licensed by States. The process of medical

licensure, making the practice of medicine without

a license a criminal offense, both permits individuals

to practice medicine and forbids those without a

license born competing. As well as providing

minimum standards, licensing of physicians provides States with the right to review an individual’s

practice and to discipline the person. Sanctions

range from simple censure to license revocation for

failure to follow proper standards in delivering

services. As such, licensing can have an impact on

the quality of services. A State license is the only one

required to practice medicine or any of its specialties. Neither failure to obtain specialty board certification nor failure to maintain membership in a

professional medical specialty society in any way

limits a physician’s legal ability to practice a

medical specialty.

Nonetheless, economic and intellectual incentives in the 1930s and 1940s led to the development

of certification procedures for specialties, to hospitalbased specialty training programs, and finally to the
Chapter 5---Quality Assurance ● 121

growth of voluntary professional medical specialty

societies (143). Genetic counselors and Ph.D. geneticists are not licensed by States, but until 1992 were

certified by the American Board of Medical Genetics (ABMG) (as are M.D. geneticists). Beginning in

1993, Ph.D. and M.D. geneticists will be certified by

ABMG, but future certification of master’ s-level

counselors is uncertain.

Factors Affecting Physician Decisions About

Cystic Fibrosis Carrier Screening

No definitive mechanism exists for determining

when physicians should routinely inform people

about the availability of tests that could reveal their

propensity to have a child with a genetic disorder,

such as CF (70). Physician practice maybe driven by

judgment of what is in a patient’s best interest,

consumer demand, patient autonomy, liability fears,

economic self-interest, or a combination of these

factors. CF carrier screening presents a classic

instance of the perennial problem of appropriately

controlling the evolution of practice standards as a

new technology becomes available,

Physicians can now offer individuals with no

family history of CF a test that can determine, with

85 to 95 percent sensitivity, whether they are CF

carriers. With professional opinion in a state of flux

and knowledge of the test’s existence continuing to

spread among patients, physicians might wonder

whether they are obligated to inform patients of its

availability, even before patients ask about it.

Determining when to routinely inform people about

the availability of tests that reveal their propensity

for having a child with CF is a contentious issue.

OTA’s survey of genetic counselors and nurses in

genetics revealed that some consumers are interested

in CF carrier screening: about 19 percent of respondents said they were “frequently’ or ‘‘very frequently’ asked by clients about DNA carrier testing

or screening for CF (170). On the other hand, some

physicians report that consumer willingness to

undertake CF carrier screening is modest at present

(1 1,13). This reticence could stem from, in part,

resistance to the tests’ costs, which patients must

generally self-pay.2 It might also arise from a barrier

common to many types of medical screening: lack of

interest and reluctance to uncover what might be

perceived as potentially unpleasant news (145).

Generally, physicians are obligated to inform

patients of the risks and benefits of proposed tests

and procedures, so that patients themselves may

decide whether to proceed. This obligation extends

to diagnostic techniques (150). Where a patient

specifically asks about a test, physicians would seem

to be obligated to discuss the test, even if they do not

recommend that it be taken. Preliminary results from

one survey, for example, indicate that up to 90

percent of physicians responding would order a CF

carrier test if asked to by a patient (76). Physicians

do not appear, however, to be obligated to ask

patients about their potential interest in a test or

procedure that the physician does not view as

warranted by individuals’ circumstances (box 5-D)

(104), although they are under an obligation to elicit

family histories that reveal whether a person is at a

particular risk for conceiving a child with a genetic

disorder.

A 1989 California appellate court held that a

couple, whose family did not appear to have

members of an ethnic group at elevated risk for

Tay-Sachs disease, had no basis to complain of

malpractice when a physician failed to inform them

that Tay-Sachs carrier screening is available (104).

Expert witnesses advised that the 1 in 167 carrier

frequency for Tay-Sachs in the general population

was sufficiently low that customary medical practice

does not recommend carrier screening for those not

at elevated risk-i. e., those who are neither Ashkenazic Jews nor descended from a few other groups

with elevated carrier incidence.

For CF, however, the incidence of carriers is more

common in the general Caucasian population (1 in

25) than is Tay-Sachs for Ashkenazic Jews (1 in 31)

(134). Physicians might ponder whether the 1 in 25

carrier frequency, which results in a 1 in 2,500

incidence of CF among live births in the general

population, is sufficiently high that they should

inform patients that CF carrier mutation analysis

Z P~ysicians seeing patients who rely on health insurance to cover part of their costs usually inform them that their coverage generally precludes

reimbursement for CF mutation analysis without a family history of the condition (i.e., for screening purposes). OTA recognizes that in the present health

care system, and with current reimbursement policies by insurers (ch. 7), the reality is that choosing to be screened usually depends on the ability to

self-pay. As mentioned earlier, however, the issue of economic access to CF carrier screening is no different-and inextricably linked--to the broad

issue of health care access in the United States (172), a topic beyond the scope of this report. In this repo~ OTA analyzes the issue in the context of

today’s health care system, but points out that in the view of some opponents of widespread CF camier screening, nonuniversal access is an a priori reason

for why CF carrier screening should not proceed.
122 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 5-D—Medical Malpractice and Standards of Care

Tort law permits individuals to sue those who have negligently caused them harm, achieving financial and

emotional compensation for some victims and providing one means of quality assurance in medical practice.

Theoretically, making providers responsible for their actions provides an incentive for them to act reasonably and

prevent patient harm. In practice, medical malpractice litigation sometimes suffers the shortcoming of juries and

judges second guessing past physician practice as a means of stimulating future improvements. In general, tort suits

do a better job of enforcing standards after they have been developed. Nevertheless, medical malpractice litigation

allows a jury to review the acts of a treating physician, remedy individual grievances, and force development of a

good practice standard.

A physician whose treatment complied with the standard of care in the field, i.e., conformed with that offered

by the “reasonable prudent physician” (or specialist, if the defendant is a specialist) under the same or similar

circumstances, can rarely be found liable for medical malpractice. Statements issued by a relevant professional

society are viewed as evidence of what a reasonably prudent physician might have done; so is expert witness

testimony (43,51,58,173). Thus, current customs of practice protect physicians. The law assumes, however, that

customary medical practice adequately reflects scientific learning and otherwise represents appropriate public

policy to be enforced by the courts against individual practitioners (70).

Yet a court can devalue a standard of care by asserting that limited adoption of a practice by some professionals

is sufficient to call into question the reasonableness of the defendant’s practice-regardless of the extent to which

that practice was accepted generally by the profession (40). The plaintiff no longer needs to show a deviation form

what the average practitioner would have done. Instead, he or she can establish negligence based only on the

defendant’s failure to do what some cohort of the same profession was doing (40,188). Even with uniform practice

within an industry (147) or profession (75,82,95), conformity with guidelines and customary practice is not an

absolute defense beeause “there are precautions so imperative that even their universal disregard will not excuse

their omission” (147).

In the context of medical care, however, only a few courts have followed this reasoning (52,71,96,149). Instead,

most courts have deferred to the usual and customay practice of the majority of similarly skilled physicians—

sometimes limiting review to local practice standards—when evaluating the actions of a particular physician

(37,101,115) 0

No empirical data exists on current customs of practice about generally informing individuals about CF carrier

tests. Physicians are somewhat protected, however, by professional society statements that advise against CF carrier

screening for all individuals. On the other hand, because the content of some professional statements are in flux and

because the technology changes quickly, a provider might worry that failure to offer the test or at least to inform

couples of the assay’s existence-will fall below rapidly evolving customs of care.

Since a variety of professionals provide genetic counseling, another question is whether the same standard of

care should apply to all. Generally, each class of health care professionals is held to a separate standard of care (24).

But this rule is premised, in part, on the notion that each group performs distinct types of services. Where the service

is identical+. g., CF carrier screening and subsequent counseling about risks by a genetic counselor, nurse, social

worker, fertility specialist, obstetrician/gynecologist, internist, or family practitioner-anyone performing the

service would be expected to meet at least a common minimum standard of care (24). Where the professional in

contact with the patient does not possess the requisite skill, that professional will be under a duty to recognize his

or her limitations and refer to the appropriate specialist (90).

SOURCE: Office of Technology Assessment, 1992.

exists. Whether physicians are obligated to do so develop during a time of diverse opinion. The policy

depends, however, - on the customary practice of

similarly skilled and situated physicians.

With respect to CF carrier screening, customary

physician practice might evolve faster than that

recommended by physicians’ own professional societies (box 5-E), by managed health care facilities or

insurance companies, or by government programs.

This raises the question of how customary practices

statements of professional societies (6,44,49) and

participants at a Government-sponsored workshop

(107) all state that CF mutation tests are not

recommended for individuals without a family

history of CF.

In addition to taking their cues from professional

society and government guidelines, physicians might

oppose informing patients of the availability of CF
Chapter 5----Quality Assurance ● 123

Box 5-E—Professional Societies and Standards of Care

Professional societies can set voluntary, informal standards for professional behavior, require members to

participate in continuing professional education to maintain active membership status, or require periodic

examination. They can have codes of ethics governing general behavior, as do the American Medical Association

(AMA) and the National Society of Genetic Counselors. A professional organization, such as the new American

College of Medical Genetics, can also survey its members and gather data on new techniques. Membership in

professional societies is voluntary, as is members’ adherence to an organization’s code of conduct and standards

and participation in membership surveys.

When faced with a complaint about malpractice, courts will generally hold that the customary practice of

similarly skilled physicians will be deemed ‘‘reasonable” care. To determine what is customary and appropriate,

courts often look to guidelines established by the relevant professional societies. Conversely, to protect their

members, customary practices are often incorporated in professional statements and guidelines.

Identification of DF508 in 1989 resulted in intense speculation about the appropriate standard of care for

general population CF carrier screening—speculation that heightens as the assay’s capability to detect prevalent

mutations improves. At the center of the discussions, professional societies faced the question: Should offering CF

carrier screening become the standard of care in medical practice?

While acknowledging that a spectrum of individual opinions exists, the American Society of Human Genetics

(ASHG), the largest professional society comprised of members of the human genetics research and clinical

communities, issued a statement in 1990 about the timing of widespread carrier screening for CF. ASHG’s

leadership, based on its own analysis and not a poll of the membership, took the position that routine CF carrier

screening is “NOT yet the standard of care” (25). The Committee on Obstetrics: Maternal and Fetal Medicine of

the American College of Obstetricians and Gynecologists endorsed the ASHG position statement soon thereafter

(44), and the AMA has also issued a similar position statement on CF carrier screening (49).

In mid-1992, after extended discussion, ASHG’s leadership approval a revised statement that CF mutation

analysis ‘‘is not recommended at this time’ for those without family histories of CF (6). Some argue that the subtle

change in language of the 1992 statement retreats from the absoluteness of the 1990 statement. This view holds that

the new statement reflects an evolution of debate within the society—that some believe CF carrier screening may

now be offered to individuals without a family history of CF, although it might not be the ‘standard of care. Others

argue that ASHG’s position is unchanged-that the new statement is tantamount to restating that CF carrier

screening should not be offered to individuals without a family history of CF. In either case, the statement cannot

be interpreted to mean that CF carrier screening should be offered to all individuals.

Professional statements can exert significant influence beyond helping courts and juries to evaluate malpractice

claims. On the basis of the first ASHG statement, at least one commercial facility initially did not promote its CF

tests for population screening purposes (56,61), although it appears to do so now. Additionally, OTA’s survey of

genetic counselors and nurses revealed that 53 percent felt in June 1991 that it was inappropriate to provide CF

carrier screening compared to 20.6 percent who believed CF carrier tests for cases of negative family history was

appropriate (20.6 percent uncertain); 74 percent of respondents knew of the ASHG statement (versus 31 percent who

knew of the NE-I statement), and many specifically cited the ASHG statement as influencing their or their

institutions’ policies.

SOURCE: Office of Technology Assessment, 1992.

carrier screening because they judge that the test is if they never worried about it when the test was

too psychologically risky to be worth any potential

benefits to those without a family history of CF. The

very existence of prenatal diagnoses can produce

stress in potential parents (89). For some patients,

tests’ availability sharpens otherwise low-level,

diffuse concerns that surface only “on bad days, ”

and turns them into real and dreaded possibilities

(89). Even with accurate delivery of statistical

information concerning the incidence of CF, people

can become worried about their carrier status--even

unavailable. The effects of this concern can be

significant, ranging from sleepless nights to hesitation about conceiving or bearing a child (131).

Physicians might also decline to screen patients

because a third-party payor or managed care provider judges the test to be too expensive for expected

benefits.

Opponents of CF carrier screening also argue that

inappropriate financial incentives drive the practice—
124 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

that physicians paid on a fee-for-service basis find

CF mutation tests profitable, as has been the case for

other diagnostic procedures (72), or contend that

physicians’ recommendations might be influenced

by laboratories marketing their tests in the same way

that pharmaceutical companies currently market

drugs to doctors (32,64). Some opponents also

express concern that increased CF carrier screening

will pressure third-party payers and managed care

facilities to provide reimbursement for the test’s

cost, thereby necessitating a rise in premiums or

discontinuation of coverage for other tests that these

opponents view as more important.

Some physicians, however, have already chosen

to incorporate (CF carrier screening into their practices because they disagree with the existing guidelines. They believe the assays are sufficiently

sensitive for general use, and that even patients with

unknown risk of conceiving a child with CF should

now have the information to exercise choice in

managing their health care. Still other physicians

might be offering the assay out of concern that

failing to could subject them to charges of medical

malpractice if a couple has a child with CF and a

court subsequently finds that CF carrier screening

had indeed become the standard of care, despite

professional statements to the contrary (19). They

may worry and practice “defensive medicine”

(171), afraid that the growing practice of offering the

test to self-paying patients—those who have specifically asked about and those who have not—sets a de

facto (and therefore de jure) standard of care for all

individuals (box 5-F).

Concerns about defensive medicine are especially

important because, although courts look to professional society statements for evidence of practice

standards, in the end it is the actual practice of

similarly skilled professionals that tends to set the

minimum threshold for reasonable care. Defensive

medicine has been blamed for the proliferation of

many other medical tests and procedures of limited

value to certain populations. The problem is particularly acute with regard to procedures performed in

the context of reproductive medicine, since the birth

of a baby with severe medical problems can result in

substantial damage awards to cover medical expenses of the child’s projected lifespan (79). CF

carrier screening seems to fall squarely within this

concern (57).

As of mid-1992, customary medical practice has

not evolved to routine CF carrier screening. Nor has

any court had occasion to consider whether the

standard of care for good medicine requires CF

carrier screening. To date, the statements of professional societies have slowed the adoption of such a

standard of care by signaling to physicians, thirdparty payers, and courts that CF carrier screening is

not necessary to meet definitions of reasonable care.

On the other hand, while no empirical data exist on

current customs of practice about informing individuals in a clinical setting about the availability CF

carrier tests, trends in the number of assays performed suggest increasing numbers of providers are

informing individuals about their availability (ch. 2).

Whether such practices will be sustained-and

hence become the standard of care-is unclear. But

if doubts about the appropriateness of CF carrier

assays fade, an obligation to offer them to all

individuals is likely to heighten (128).

Clearly, a balance among professional guidelines,

physician views, and patient demand must be struck

with regard to CF carrier screening. Overall, physicians acting on behalf of individuals will establish

customs of care. Nevertheless, standard setting in

the area of medical practice is diffuse and generally

unregulated. In the end it might be up to courts and

juries to determine, on a case-by-case basis through

retrospective review in the context of medical

malpractice litigation, what level of care is owed to

patients.

Duties of Care for Genetic Counseling

Genetic counseling requires professionals to educate patients about the availability of genetic services, to elicit enough information to determine

whether patients are in particular need of genetic

tests, to help patients decide whether genetic information would be useful to them, especially in light

of their personal and religious values, and to assist

patients in obtaining quality genetic analysis if

desired.

A decision to offer information about tests for CF

carrier screeninger to provide the assay itself—

raises questions: What constitutes quality genetic

counseling? What about confidentiality of information obtained in the course of counseling?
Chapter 5---Quality Assurance ● 125

Box 5-F—The Maine Medical Liability Demonstration Project:

An Alternative Approach to Set Practice Standards?

In response to concerns about defensive medicine, Maine enacted legislation in 1990 that creates a

demonstration project designed to ensure high quality medical care, to reduce costs associated with medical

malpractice litigation, and to decrease incentives to practice defensive medicine. The project hopes to accomplish

these goals by having groups of physicians work with representatives of patients and insurers to form consensus

opinions on practice standards in defined areas of medical care. These practice standards are then available to

participating physians in the form of professional education. If a participating physician complies with the practice

standards, then he or she is largely protected from claims of medical malpractice.

Advisory committees in a particular area of practice will be composed of experts relevant to the area as well

as public members. For example, the Medical Specialty Advisory Committee on Obstetrics and Gynecology

consists of nine members, including six physicians representing diverse interests (e.g., a tertiary hospital, mid-sized

hospital, and rural practice) and three public members (one representing the interests of payers of medical costs,

one representing consumers, and a representative of allied health professionals).

Each medical specialty advisory committee shall develop practice parameters and risk management protocols

in the area relating to that committee. Practice parameters must define appropriate clinical indications and methods

of treatment within that specialty. Risk management protocols must establish standards of practice designed to avoid

malpractice claims and increase the defensibility of those that are pursued. Once the medical specialty advisory

committee recommends a set of actions, the Board of Registration in Medicine and the Board of Osteopathic

Examination and Registration shall review and approve the parameters and protocols for each medical specialty

area, and adopt them as rules under the Maine Administrative Procedure Act. Each medical specialty advisory

committee shall also provide a report to the Legislature setting forth the parameters and protocols that have been

adopted, and describe the extent to which the risk management protocols reduce the practice of defensive medicine.

For claims of professional negligence against a participating physician (or the employer of a participating

physician) that allege a violation of the standard of care, only the participating physician (or the physician’s

employer) may introduce into evidence, as an affirmative defense, the existence of the practice parameters and risk

management protocols developed and adopted for that medical specialty area. Unless independently developed from

a source other than the demonstration project, the practice parameters and risk management protocols are not

admissible in evidence in a lawsuit against any physician who is not a participant in the demonstration project.

For malpractice policies beginning on or after July 1, 1990, the State superintendent of insurance shall

determine the amount of the savings in professional liability insurance claims and claim settlement costs to insurers

anticipated in each 12-month period as a result of the project. A portion of the savings could be subject to an

assessment that would be used to address other health care needs of the State.

The Maine project represents an innovative approach to questions raised about appropriate medical practice

standards. It formalizes the role of professional societies in establishing standards of care, giving them statutory

authority and protection. It also expands the decisionmaking process to explicitly include members of the public.

As the project progresses, it could provide interesting perspectives and results in the area of standards of care and

medical liability to policymakers.

SOURCE: Office of Technology Assessrnent, 1992, based on Title 24. Insumnc e, Chapter 21. Maine Health Security Act, Subchapter IX.

Medical Liability Demonstration Project, 24 M.R.S. 2971 (1990).

Pretestin — g—

To meet standards of responsible care, a genetics

professional must understand enough about the

patient’s health and his or her reproductive plans.

The provider must also be aware of what technologies are available to take an appropriate family

history and proceed with necessary analyses. For a

nonspecialist, it might be enough to recognize the

need for a referral (24,106). These tasks have

become more difficult as the timing for genetic

affected child to prior to a patient’s frost conception.

Thus, the usual signal of a patient at risk (i.e., the

birth of an affected child) would not be present.

Today, providers might elicit information concerning a patient’s plans with regard to children and

family history for a wide variety of detectable

disorders, some of which are quite rare, during

general checkups and annual gynecological visits.

This would then be followed by client education to
126 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

help individuals decide whether they wish to pursue

further counseling or tests. Less than that could give

patients grounds to complain of a false assurance of

safety.

Counseling

Having elicited information and obtained test

results, the professional’s next task is to communicate the results in a meaningful way. An important

aspect of this task involves explaining the reproductive risks clients face. Because statistical information can be difficult to understand, this responsibility

is more complex than merely stating the odds that a

child will be born with a genetic condition.

All professionals who do genetic counseling—

genetic counselors, nurses, doctors, social workers,

and clinical geneticists—realize that translating

technically accurate information into understandable information is essential and difficult (63,91,

114,124,130,137,179). Making information meaningful to nonprofessionals includes :

●

●

●

●

●

●

supplying an accurate, or at least tentative,

diagnosis;

explaining the pattern of inheritance along with

known uncertainties;

recognizing and understanding psychosocial

and ethnocultural issues;

presenting the range of therapeutic options for

treatment and management of the disorder;

offering options for further diagnostic tests, if

available; and

counseling on medical options for preventing

the birth of affected children, if desired by the

patient (1,7,24,1 11,123,178).

Judging whether information has been delivered

in a sufficiently comprehensible way is not simple.

People interpret information about genetic risk in a

highly personal manner (93,183), and a counselee

can misperceive, misunderstand, or distort information. Such an effect could have significant emotional

impact that affects the individual’s decisionmaking

or adjustment to the circumstance (131,176,179).

Some consumers could perceive that a negative

result from the use of “cutting edge’ DNA technology means no risk, thus mistakenly interpreting the

assay’s resolution. Still others might believe that

administration of the test itself conveys protection

from risk.

In one study on risk communication and patient

interpretation, over one-quarter of women surveyed

Photo credit: Beth Fine

A genetic counselor discusses results with clients. Genetic

counseling can help individuals and families understand

the implications of positive and negative test outcomes.

could not correctly explain the meaning of 1 out of

1,000. Of those who gave the correct answer, 16

percent said the defect occurred “often or occasionally,” versus “rarely or very rarely. ’ Thirty-one

percent of those who incorrectly answered the

question judged the defect occurred “often or

occasionally’ (26). Another study of clients showed

that those perceiving their numerical risk as higher

than others who were at the same risk were more

likely to ask the genetic counselor about having

another child. At the same time, patients tend to

interpret a given mathematical risk as ‘‘low’ more

often than do the counselors describing it (183).

Finally, leaving the mathematical ability of patients

aside, parents’ perceptions of uncertainty in genetic

counseling significantly affects qualitative decisions

they make (94).

Given the nuances of information delivery and

reception, and differences in situations encountered,

is there a standard for genetic counseling? One

commentator argues in favor of a standard for

genetic counseling based on what patients would

want to know (modeled after informed consent

requirements) because there is no freed professional

norm as an alternative, and because adequacy of the

information conveyed turns more on the values of

the patient being counseled than on professional

norms: “It seems proper for a counselor to aim at

informin g the counselees about everything the latter

would find material to the decision they have to

make as determined on the basis of a lay, not expert,
Chapter S--Quality Assurance . 127

standard’ (24). The more prevalent standard, however, appears to be based on a review of what most

professionals do, rather than what an individual

patient wants (29,87), The problem with relying

solely on professional custom is that standards are

still evolving, and there are distinctive schools of

thought about methods of counseling (78,137,142).

In light of the 1991 Supreme Court decision in

Rust v. Sullivan (132), it is unlikely that patients at

a clinic receiving Federal funds from Title X of the

Public Health Service Act could easily receive

information about the option of choosing to terminate a pregnancy that is at risk of resulting in the

birth of a child with a genetic disorder. This judicial

decision runs counter to beliefs of many in the

genetics community: ASHG members overwhelmingly assert that genetic counseling about all reproductive options is imperative (4). Rust uphel d

Federal regulation requiring clinics receiving these

monies to respond to all inquiries concerning

abortion by stating that abortion is not an appropriate

family planning option. In the context of genetic

counseling, many argued that the rule is inconsistent

with the standards of medical care required by State

malpractice statutes and cases—i, e., that abortion is

within the range of options that physicians and

health care providers are expected to disclose to their

patients (23). In March 1992, the rule was reinterpreted to permit physicians to discuss abortion, but

it does not permit them to counsel where it can be

obtained. Nurses and counselors may not discuss

abortion. As the vast majority of interactions at

clinics receiving Title X funds are between patients

and nurses, the reinterpretation will have limited

effect on counseling practices.

Depending on the condition, pregnancy termination is chosen by 57 to 97 percent of parents who

learn that a fetus will be born with a genetic disorder

(16,41,50,62). A 1990 general survey of the American public found 32 percent of respondents would

undergo an abortion if a genetic test proved positive;

an additional 18 percent reported that having an

abortion would depend on the nature of the defect

(140). With respect to CF specifically, a recent

sampling in New England of parents who had a child

with CF found 80 percent would continue a pregnancy even if prenatal testing determined that the

fetus was affected, although the majority said

abortion should be a legally available option for

those who utilize such testing (181,182). Another

study of families who had children with CF in the

Rochester, NY area found 56 percent approved that

a woman should have the option of termin ating

CF-affected pregnancies, but the question did not

ask whether they, themselves, would (102). No data

on general population attitudes (no family history)

toward CF carrier screening, prenatal diagnosis, and

abortion exist, but data are accumulating from a

limited number of experiences in CF carrier screening pilots. Indications are that, compared to couples

with family histories of CF, fewer individuals from

the general population would continue an affected

pregnancy (14,21).

The 1992 U.S. Supreme Court decision in

Planned Parenthood of Southeastern Pennsylvania

v. Casey3 means abortion now turns largely on State

law, although it also appears that absolute obstacles

to such a choice will be held unconstitutional. At

issue was the 1973 decision in Roe v. Wade (129),

which held a woman’s liberty of conscience and

bodily integrity may not be sacrificed to State

interests in protecting fetal life. The 1992 decision

announced such liberty remains protected from State

efforts to prohibit abortion, but States now may

make a woman’s choice to terminate a pregnancy

following prenatal diagnosis more financially, medically, or emotionally difficult unless the restriction

is a substantial obstacle to choosing abortion. This

new standard, the ‘‘undue burden’ test, represents a

retreat from the standard in Roe, which held that

abortion was a fundamental right. As a fundamental

right, abortion was protected horn all State impediments except those based on a compelling need and

implemented in the least restrictive manner possible—the “strict scrutiny” test. The new standard

requires empirical data as to the effect of State

regulations on women’s ability to choose pregnancy

terminations, Thus, State regulations restricting or

shaping genetic counseling might be evaluated to

determine if they pose a ‘‘substantial’ obstacle to a

woman’s choice of pregnancy termination. The

1992 opinion appears to tolerate a potentially wide

range of State laws that might be enacted t o

discourage women from using prenatal testing or

aborting affected fetuses. The decision explicitly

upholds the constitutionality of State preferences for

childbirth over abortion throughout pregnancy, and

not merely following viability.

~ Plunncd Parenlh(]od of .T(mrheusrer-n Penn.~)l\’ania v. Case>, —S.Ct.— ( 1992), 60 U. S.L.W. 4795.
128 . Cystic Fibrosis and DNA Tests: Implications of Carrrier Screening

Keeping Genetic Information Confidential

Both ethics and law obligate professionals with

information on the carrier or affected status of a

patient to keep that information confidential absent

a few, specific exceptions (3,8,60,88,187). Professional codes of ethics guide practitioners (3,109), as

do State statutes or case law in States with no

specific statutory authority (27,67,68,77,110,139).

Not all genetic information must remain confidential, however.

A patient is presumed to have consented to

disclosure to his or her partner, for example, if the

individual comes in for genetic counseling as part of

a couple and the initial history is performed on both

partners. Similarly, consent to disclosure is generally assumed when test results are raised as an issue

in a malpractice suit or in an appeal for benefits

denied by a govemment agency (126). State statutes

also require that certain medical findings be reported, such as certain birth defects or communicable diseases, sexual and physical abuse of children,

gunshot wounds, and drug abuse (8,60). At least 12

States require that birth defects be reported to a

registry (Florida, Indiana, Iowa, Louisiana, Maryland, Michigan, Minnesota, New Jersey, Virginia,

Washington, West Virginia, and Wisconsin).A

The closest analogy to a situation in which a

provider might wish to reveal genetic information to

third parties without a patient’s permission appears

to be the case of disclosure of communicable

diseases. As with disclosing a risk of infection, the

motivation would be to spare third parties the ill

effects of the disorder. In the case of CF, this would

entail a wish to help relatives of the patient be aware

that they, too, could beat higher than average risk of

conceiving a child with CF. If, after a patient has

been advised to inform relatives that they could

carry a CF mutation, the provider is persuaded that

the relatives will not be notified, he or she may want

to breach confidentiality. The impulse to breach

confidentiality could be legal as well as humanitarian. Genetics providers might be concerned that they

have a legal duty to protect third parties from

intentional, foreseeable harm when they know that

President’s Commission for the Study of

Ethical Problems in Medicine and

Biomedlcal and Behavioral Research

Photo credit: office of Thehnology Assessment

A 1983 report of the President’s Commission for the

Study of Ethical Problems in Medicine and Biomedical and

Behavioral Research.

one of their patients poses a threat (146), although

courts still narrowly construe such a duty.

From an ethical perspective, the 1983 President’s

Commission delineated four conditions that should

be satisfied before overriding confidentiality with

regards to genetic information. First, reasonable

efforts to elicit voluntary consent for disclosure have

failed. Second, a high probability exists that harm

will occur if the information is withheld and that the

disclosed information will actually be used to avert

harm. Third, the harm that identifiable individuals

would suffer would be serious. Fourth, appropriate

precautions are taken to ensure that only the genetic

4 ~Oli& Stat. Ann. Sec. 41 1.203(9)(b) (West 1986); ~Oli& Adxn.uL“ Code. Ann. R. 1OJ-8.OO7 (1990) and Guideline VII(b) (1981); Indiana Stat.

Ann. See. 164101 (Michie 1990); Iowa Code Ann. Sec. 136A.6 (West 1989); Louisiana Department of Health and Human Services, Guidelines:

Neonatal Scnxming, Sec. III(F) (1988); Ma@and Regs. Code Tit. 10, Sec. 10.38.11 (1975); Michigan Comp. IAws 333.5721 (1990); Minnesota Reg.

7.1.172(c)(2)(b) (1979); New Jersey Stat. Sec. 26:840.22 (1989); Virginia Code Ann. 32.1 -69.1 (1990); Wash. Rev. Code Sec. 70,58.320 (1990); West

Virginia Code Sec. 16-5-12a (Michie 1990); Wisconsin Stat. Sec. 146.028 (1987-88).
Chapter 5---Quality Assurance ● 129

information needed for diagnosis or treatment of the

condition in question is disclosed (119).

Evaluating CF carrier screening in light of the

President’s Commission’s criteria reveals that:

●

●

●

The patient is not the source of the danger to the

third party, as is the case with communicable

disease. Rather, the patient’s carrier status is

merely an indication that the mutation is

present in the family and that each blood

relative is at increased risk of being a carrier.

Even if the relative is a carrier, it poses no threat

to his or her person because only those carrying two copies of the mutation exhibit any ill

effects. Being a carrier carries no personal

threat of illness.

Being a carrier does not pose a problem in

reproductive planning unless the relative’s

partner is also a carrier.

Overall, then, the risk to the third party from

nondisclosure must be balanced against the benefit

of maintaining the expected confidentiality of the

provider-patient setting. A provider contemplating

breach of confidentiality and disclosure to a patient’s spouse must weigh the patient’s own confidentiality against the spouse’s interest in sharing

decisions concerning conception, abortion, or preparation for the birth of a child with extraordinary

medical needs. For CF, the chances of harm also

must be evaluated: The spouse must also be a CF

carrier for the probability of having a child with CF

to rise to 25 percent.

In actual practice, a recent international survey of

M.D. and Ph.D. geneticists revealed that 60 percent

of respondents in the United States (and 66 percent

from 17 other countries) said they would disclose a

child’s diagnosis of hemophilia A to interested

maternal relatives who might be at risk for conceiving children with hemophilia A—against the wishes

of the client. Twenty-four percent of respondents

would seek out relatives and tell them even if they

did not ask for the information (180), (Hemophilia A

is an X-linked, recessive disorder, and hence carriers

are only female. For CF, both paternal and maternal

relatives could be carriers. Hence, the situation is not

strictly equivalent, but is illustrative for CF carrier

screening. )

Finally, as important as maintaining confidentiality of CF carrier status within families, is confidentiality with respect to third parties. At least one life

insurance group acknowledges that existing mechanisms to maintain confidentiality of genetic test

information might not be appropriate, and that

special protection might be necessary (2). Recent

evidence indicates that the Cystic Fibrosis Foundation (CFF), as part of its annual survey of CF centers,

has begun to request information on mutation status

(31,174). CFF releases only aggregate information

for research purposes, but because data are delivered

by centers to CFF without express consent in a

fashion that is identifiable to individuals and their

families, questions about the advisability of this

practice have arisen. A sampling of institutions

reveals that institutional review boards have not

reviewed such practices nor been consulted about

releasing such information (31).

Compensation for Inadequate

Genetic Counseling

Practitioners who provide inadequate genetic

counseling, including failing to prescribe needed

tests or failing to keep results confidential, might be

subject to sanctions by a regulatory body or a

professional society. As with other areas of civil law

enforcement, sanctions can range from a mild

reprimand to revocation of applicable licenses to

practice. Courts also can issue an injunction to

prevent a practitioner from disclosing certain information, on pain of being found in contempt of court.

Finally, courts (and juries) can award monetary

compensation for out-of-pocket expenses and mental or physical suffering to those harmed by poor

counseling. In particularly outrageous cases, punitive damages may be assessed against a defendant.

Failure to Adequately Test or Counsel

People are human and mistakes are made. But

what happens when the birth of an affected child

occurs because a health professional breaches a duty

to adequately test or counsel a client? Increasingly,

courts have become arbiters of whether a health care

provider has met his or her professional obligations

to a patient, which has increased the impact of

judicial decisionmaking on quality assurance of

professional services.

Inadequate counseling for genetic tests can result

in a number of outcomes. First, patients might

forego conception or terminate a pregnancy when

correct information would have reassured them.

Second, people might choose to conceive children

when they otherwise would have practiced contra-
130 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

ception, they might fail to investigate using donor

gametes that are free of the genetic trait they wish to

avoid, or they might lose the opportunity to choose

to terminate a pregnancy. The latter situations could

result in the unwanted birth of an affected child.

Medical personnel have a duty to provide information to expectant parents so that they can be fully

informed about any reproductive decision they

choose to make (17,20,24,39,86,105,125, 127).

Courts have also occasionally recognized a duty for

health care providers (and even parents) to prevent

persons not yet conceived from being conceived in

a manner that would result in their birth under

conditions where they would suffer serious genetic

or congenital disorders (36,69).

Wrongful Birth and Wrongful Life. Wrongful

birth and wrongful life are the terms used to describe

the forms of malpractice claims that arise from the

birth of an affected child. In a wrongful birth claim,

parents assert that failure to receive timely, accurate

information robbed them of the opportunity to avoid

conception or birth of an affected child. Wrongful

birth claims can result in special danages (usually

medical expenses and other special costs associated

with the care of an affected child) and general

damages (those encompassing all the ordinary costs

of raising the child). Since the 1973 Roe v. Wad e

decision (129), courts tend to award special danages

when a case has merit.5 Most courts remain reluctant

to award general damages.

Although some courts have rejected the wrongful

birth claim altogether (10,86), most jurisdictions

allow compensation to parents for the negligent

failure to inform or to provide correct information in

time for them to either prevent conception or to

decide whether to terminate a pregnancy if a fetus

shows evidence of a genetic disorder. Rarely have

State legislatures acted to categorically deny parents

access to wrongful birth claims,6 except to forbid

claims based on allegations that the parents would

have terminated the pregnancy had they been

adequately counseled and tested.7 Such State statutes limit parental claims for wrongful birth to cases

of preconception counseling and testing that result in

parental loss of opportunity to forego conception in

favor of adoption or the use of donor gametes.

With regard to CF, at least one court has ruled that

parents might collect the extra medical costs associated with managing the condition. In this case, the

couple complained that they would have avoided

conceiving a second child had their physicians

accurately diagnosed CF in their first child and thus

realized both parents were carriers (136).

In wrongful life claims, the child asserts he or she

was harmed by the failure to give the parents an

opportunity to avoid conception or birth, because

never having existed would be better than to exist

with severe disabilities. U.S. courts, however, have

been reluctant to allow damages because most have

been uncomfortable with any decision that hints

nonexistence might be preferable to life, even when

that life includes pain and suffering.

As of 1991, courts in only three States recognized

a cause of action for wrongful life: California (15 1),

New Jersey (120), and Washington (69). The status

of the cause of action is unclear in Louisiana and

Indiana, whose courts have held that physicians do

have a duty to advise parents prior to conception that

they have an elevated risk of giving birth to a

severely afflicted child and that a wrongful life

action might be an appropriate remedy for the child

(33,1 18).8 In contrast, 21 States have judicially

rejected a common law cause of action for wrongful

5 Should Roe v. Wude ultimately be overturned, wrongful birth and wrongful life cases would again tum largely on State abortion law. Where

abortion becomes illegal, State courts could conclude that failure to inform a woman of significant fetal abnormalities does not deprive her of the choice

to terminate the pregnancy, as that choice is foreclosed by State law. Since it is unlikely, however, that all States would outlaw abortioni the ability to

travel to a jurisdiction where abortion remained legal could lead courts to conclude that an opportunity nonetheless had been lost due to a faulty diagnosis

of genetic impairment. Thus, while wrongful life and wrongful birth claims might be weakened by overturning Roe v. Wade, they would not be

eliminated. The ASHG recently endorsed model statutory language designed to protect the reproductive options of women at risk for bearing children

with serious genetic or congenital disorders (5).

b Colorado Stat. Sec. 13-64-502.

7 Mimesota Stat, Ann. Sec. 145; Missouri Am. Stat. Sec. 188.130; South Dakota Stat. Sec. 21-55-2; Utah Stat. Sec. 78-11-24 (30).

8 In he Indiana ca5e, me Coun held tit me state statute prohibiting wrongful life suits applied only when the c~ld assefied he or she should have

been aborted. By its terms, the statute did not prohibit suits that claim the child should never have been conceived (33).

s Alabama (45); Arizona (177); Colorado (92); Delaware (59); Florida (103); Georgia (9,55); Idaho (18); Illinois (1 38); Kansas (22); Kentucky

(135); Massachusetts (175); Michigan (121); Missouri (186); New Hampshire (141); New York (15); North Carolina (10); Pennsylvania (46); South

Carolina (1 17); Texas (1 12); West Virginia (80); Wisconsin (42)
Chapter S-Quality Assurance . 131

life. 9 At least eight State statutes prohibit a cause of

action against a physician for wrongful life.l0

Overall, then, parents can sue successfully for

extraordinary medical costs associated with the birth

of a child with a disability whom they would not

have conceived or carried to term if they had

received timely, accurate information about the risks

the pregnancy posed to the affected child and to their

own emotional and financial stability. Ordinary

costs of raising the infant, however, usually are not

reimbursed. Children suing on their own behalf for

wrongful life are far less successful; most courts are

unable to conclude that they have been harmed by

living with severe disabilities when the only alternative is never to have lived.

Breach of Confidentiality

At least 21 State statutes explicitly protect patient

“formation regarding medical conditions and treatment.11 Offending physicians can have their licenses

revoked or be subject to other disciplinary action.

Four of these States—Illinois, New Mexico, North

Dakota, and Oregon-punish both negligent and

willful disclosures, Idaho and Michigan do not

differentiate between the two types of disclosure,

and the remainder punish only willful breaches of

confidentiality (8).

Patients whose confidential records have been

revealed can also bring civil suit against the physician or facility for tortious public disclosure of

private facts (122). This is not the same as a suit for

defamation, which requires that the information

divulged be false; it merely requires that the

disclosure offend community standards of decency

or expectations of privacy (12,68). Like defamation,

however, the plaintiff must demonstrate an actual

harm before compensation can be awarded.

Other civil suits a patient could bring for breach

of confidentiality include a breach of contract action.

While not common, such suits have been recognized

as legitimate by State courts (68,77,97). They are

premised on the notion that the provider-patient

relationship is contractual, and that breach of

contract litigation may be used to enforce the

implied contract of confidentiality-for example

through an injunction or, alternatively, to obtain

financial redress following an unauthorized disclosure (8,1 13). Actions brought under breach of

contract would also be possible against employees

and nonphysician health care workers, either because these individuals are party to the contractual

relationship (e.g., clerks at a medical facility) or

under a theory of respondent superior (24).

Some suits for unauthorized disclosure could be

premised on Federal and State guarantees of a right

to privacy, thus limiting the ability of government

agencies, such as health departments, to obtain

medical records (116,133). In addition, several

States have statutes that protect the confidentiality of

medical records, independent from State licensure

and discipline legislation.12

Health care professionals who release genetic or

other medical information about a patient, however,

would not be legally liable to that patient or subject

to disciplinary action if there were a valid defense to

the action. Such defenses would include the consent

of the patient, waiver of the right to object to

disclosure, the need to comply with a valid State or

Federal law, or, at times, the need to prevent physical

harm to a third party, as discussed earlier.

SUMMARY AND CONCLUSIONS

Quality assurance for CF carrier screening means

ensuring the safety and efficacy of the tests themselves, whether they are performed de novo in

10 ~dlaa code ~, sec. 34-1.1.11 @um~ Supp 1989); Maine Rev, s~t. AIM. Tit. 24, sec. 2931 (supp. 1989); Minnesom Smt. Ann. Sec. 145.42 4

(West 1990); Missouri Ann. Stat. Sec. 188.1301 (Vernon Supp. 1990); North Dakota Cent. Code Sec. 32-03-43 (Supp. 1989); Pennsylvania 42 C.S.

Sec. 8305 (Supp. 1991); South Dakota Codified Laws Sec. 21-55-1 (1987); Utah Code Ann. Sec. 78-11-24 (Supp. 1989).

11 mom, Rev, s~t, ~.Secs sz-l~l(z(-))(b), -1451 (Supp. 1990); -sas, Stit. Ann. Sec. 17-93-44)9(15) (1987); California, BUS. and Prof.

Code Sees. 2227, 2228 (West Supp. 1991) and 2263 (West Supp. 1990); Delaware, Code AM. Tit. 24, Sec. 173(a), (b)(12) (1987); Idaho, Code Sec.

54-1814(13) (1988); Illinois, Ann. Stat. ch. 111, pa-m. @O@22(A)(30) (Smiti-Hurd Supp. 1990); Kansas, Stat. Ann. Sec. 65.2386(c) (Supp. 1989);

Kentucky, Rev. Stat. Ann. Sec. 311-595 (Baldwin Supp. 1990); Maine, Rev. Stat. Ann. Tit. 32, Sec. 3282-A(2) (Supp. 1990); Michigan, Comp. Laws

Ann. Sec. 333.16221 (e)(ii) (West Supp. 1990); Minnesot% Stat. Ann. Sec. 147-091(l)(m) (West 1989); Nebras@ Rev. Stat. Sees. 71-147(10), 71-148(9)

(1990); Nevada, Rev. Stat. AM. Sec. 6303065(1) (1989); New Mexico, Stat. AM. Sec. 61-6-15@)(5) (1989); NoM D*ot& c~t. Code SeC.

43-17 -3](13) (SUpp. 1990); Ohio, Rev. Code Ann. Sec. 4731.22 03)(4) (Baldwin 1987); OUahom~ Stat.~. Tit. 59, SeCS. 503, 5@(4) west 1989);

Oregon, Rev. Stat. Sec. 677.190(5) (1989); South Dakota, Codified Laws Arm. Sees. 36-429 (1986) and 36-4-30(4) (Supp. 1990); ‘lknnessee, Code Ann.

Sec. 63-1-120(15) ~1990); U@ Code Ann. Sees. 58-12-35(l)(a), 56-12-36(3) (1990).

12 c~ifomla Civil Cde Sm, 56,10 (West 1988); Mon~ Code ~, Sec. 50-15-525 (1987); Rhode Island Gen’1 hwS Sees. 5-37.3-1 tO .3-1 I

(1987); Wisconsin Stat. Ann. Sec. 146.82 (West 1987).
132 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

clinical diagnostic laboratories or via test kits. It also

encompasses guarantees for accurate interpretation

of the test results by health care professionals.

Ensuring that consumers receive high-quality technical and professional service for DNA-based CF

carrier tests is the responsibility of providers, under

the shared oversight of the Federal Government,

State and local governments, private entities, including professional societies, and the courts.

Quality assurance to assess clinical laboratory

performance is still in flux, in large measure because

the 1967 legislation governing regulation of clinical

testing facilities was overhauled by Congress in

1988. Rulemaking by the executive branch is under

way for some aspects of clinical laboratory regulation, but not others. The Health Care Finance

Administration hopes to propose rules, for example,

on proficiency testing, a key quality assurance

component, by the end of 1992.

The Clinical Laboratory Improvement Amendments of 1988 clearly encompass facilities performing DNA-based genetic analyses. But, while CLIA

details particular performance standards for several

types of clinical diagnostic procedures, it does not

specifically address DNA-based tests. This lack of

detailed directives for DNA-based diagnostics could

be a strength in the short-term, since the field is

rapidly changing. Whereas a predominant Federal

role appears the likely result for certain clinical

laboratory protocols, multiple stakeholders might

ultimately share oversight of DNA-based genetic

assays (e.g., CF carrier tests). For example, the

efforts of New York State in the area of genetic test

laboratory certification and proficiency testing could

influence the Federal approach to regulating genetic

analyses. Similarly, the impact of professional

organizations (e.g., the College of American Pathologists, the Council of Regional Networks for Genetic Services, and the American Society of Human

Genetics) on proficiency testing will be important.

To a certain extent, truly broad dissemination of

CF carrier screening depends on the availability of

test kits now under development. Such kits will be

subject to regulation by the U.S. Food and Drug

Administration. Since no DNA-based genetic diagnostic test kit comparable to that being developed for

CF carrier assays exists, it is difficult to predict what

regulatory status will evolve for such kits. Two

events could, however, serve as a gauge: The

enactment of the Safe Medical Devices Act of 1990,

which reflected congressional response to concern

about FDA’s oversight of medical devices, and

indications that FDA is increasing medical device

regulation and postmarketing surveillance. If congressional intent is served and increased FDA

scrutiny is extended to DNA-based diagnostic test

kits, developers can expect more stringent regulation

of their products than previous non-DNA genetic

tests (e.g., assays for abnormal hemoglobinopathies). Increased regulation could, in turn, slow the

implementation of widespread CF carrier screening,

since the availability of an easy, quick kit-similar

to what exists for maternal serum alpha-fetoprotein

screening-would otherwise facilitate screening individuals in primary care settings.

Finally, quality assurance for CF carrier screening

ultimately depends on the interaction of the health

care professional with the client. Customs of care are

still evolving regarding the obligation of physicians,

genetic counselors, and other health professionals to

inform individuals about the availability of CF

carrier screening. Although professional societies

and government advisory bodies currently state that

CF mutation assays are too imperfect to be used in

the general population, physicians are nonetheless

free to offer information and screening. Absent

consistent resistance on the part of insurers to

reimburse for the assays, it would appear that

practitioner interest, patient demand, and the perceived threat of medical malpractice litigation will

encourage some physicians and genetic counselors

to offer information about CF carrier screening to a

larger population than that recommended by their

own professional societies. The increase in information concerning patients’ genetic backgrounds can

be expected to increase the number of situations in

which health professionals will need to balance

confidentiality of patient information against demand from relatives and other third parties for access

to that information.

1.

2.

CHAPTER 5 REFERENCES

Allen, C. C., Murray, R.F., Quinton, B.A., et al.,

“Adapting Genetic Counseling to Meet the Needs

of Black Americans in the District of Columbia,’

Journal of Genetic Counseling 1:93-94, 1992.

American Council of Life Insurance, Genetic Test

Information and Insurance: Confidentiality Concerns and Recommendations (Washington, DC:

American Council of Life Insurance, 1992).
Chapter 5+uality Assurance . 133

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

American Medical Association, Current Opinions

of the Judicial Council of the American Medical

Association (1984).

American Society of Human Genetics, “American

Society of Human Genetics Statement on Clinical

Genetics and Freedom of Choice,’ American Journal of Human Genetics 48:1011, 1991.

American Society of Human Genetics, “Genetic

Services Committee Update: Report on ASHG/

CAP Joint Proficiency Testing” (Rockville, MD:

American Society of Human Genetics, 1991).

American Society of Human Genetics, “Statement

of the American Society of Human Genetics on

Cystic Fibrosis Carrier Screening,” personal communication, June 1992.

American Society of Human Genetics, Ad Hoc

Committee on Genetic Counseling, ‘Genetic Counseling,” American Journal of Human Genetics

27:240-241, 1975.

Andrews, L., and Jaeger, A., “Confidentiality of

Genetic Information in the Workplace,” American

Journal of Luw andhledicine 17:75-108, 1991.

Atlanta Obstetrics and Gynecology Group v. Abelson, 955-2-C (S. Ct. Ga. 12/5/90).

Azzolino v. Din~elder, 315 N.C. 103, 337 S.E. 2d

528 (1985), cert. denied 479 U.S. 835 (1986).

Barathur, R., Roche Biomedical Laboratories, Raritan, NJ, personal communication, September 1991.

Bazemore v. Savannah Hospital, 171 Ga. 257, 155

S.E. 194 (1930).

Beaudet, A. L., Howard Hughes Medical Institute,

Houston, TX, remarks at the 8th International

Congress of Human Genetics, Washington, DC,

October 1991.

Beaduet, A. L., Howard Hughes Medical Institute,

Houston, TX, personal communication, March

1992.

Becker v. Schwartz, 46 N.Y. 2d 401, 386 N.E. 2d

807,413 N.Y.S. 2d 895 (1978).

Berm, P. A., Hsu, L. Y. F., Carlson, A., et al., “The

Centralized Prenatal Genetics Screening Program

of New York City: III, The First 7,000 Cases, ”

American Journal of Medical Genetics 20:369-384,

1985.

Bergstresser v. Mitchell, 577 F,2d 22 (8th Cir.

1978).

Blake v. Cruz, 108 Idaho 253,698 P.2d 315 (1984).

Blumenthal, D., and Zeckhauser, R., “Genetic

Diagnosis: Implications for Medical Practice,”

International Journal of Technology Assessment in

Health Care 5:579-600, 1989.

Bonbrest v, Kotz, 65 F. Supp. 138 (D.D.C. 1946).

Botkin, J. R., and Alemagno, S., ‘Carrier Screening

for Cystic Fibrosis: A Pilot Study of the Attitudes of

Pregnant Women,” American Journal of Public

Health 82:723-725, 1992.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39,

40.

41.

42.

Bruggeman v. Schimke, 239 Kan. 245,718 P.2ci 635

(1986).

Canterbury v. Spence, 464 F.2d 772 (D.C. Cir.),

cert. denied, 409 U.S. 1064 (1972).

Capron, A.M., “Tort Liability in Genetic Counseling,” Columbia Luw Review 79:618-684, 1979.

Caskey, C.T., Kabac~ M.M., and Beaudet, A.L.,

‘‘The American Society of Human Genetics Statement on Cystic Fibrosis Screening, ” Arnericarz

Journal of Human Genetics 46:393, 1990.

Chase, G. A., Faden, R.R., Holtzrnan, N.A., et al.,

‘‘Assessment of Risk by Pregnant Women: Implications for Genetic Counseling and Education, ”

Social Biology 33:57-64, 1986.

Clark v. Geraci, 29 Misc. 2d 791, 208 N.Y.S. 2d

564 (Sup. Ct. 1960).

Clarke, A., ‘‘Is Non-Directive Genetic Counseling

Possible?,” Luncet 338:998-1001, 1991.

Clayton, E. W., The Vimderbilt Clinic, Nashville,

TN, personal communication, December 1991.

Clayton, E. W., “Reproductive Genetic Testing:

Regulatory and Liability Issues,” FetaZ Diagnosis

and Therapy in press, 1992.

Collins, D., University of Kansas Medical Center,

Kansas City, KS, personal communication, February 1992.

Consumer Reports, “Pushing Drugs to Doctors,”

February 1992, pp. 87-94.

Cowe v. Forum Group, Inc., 541 N.E. 2d 962 (hi.

App. 1989).

Cunningham, G. C., Genetic Disease Branch, California Department of Health Services, Berkeley,

CA, personal communication, December 1991.

Cunningham, G. C., and Kizer, K. W., “Maternal

Serum Alpha-Fetoprotein Screening Activities of

State Health Agencies: A Sumey,” American

Journal of Human Genetics 47:899-903, 1990.

Curlender v. Bioscience Laboratories, 106 Cal.

App. 3d811, 165 Cal. Rptr. 477 (1980).

Danzon, P., Medical Malpractice: Theory, Evidence, and Public Policy (Cambridge, MA: Harvard

University Press, 1985).

Davis, J. G,, New York Hospital, New York, NY,

personal communication, October 1991.

DeWalt, T., “Wrongful Life and Wrongful Birth:

The Current Status of Negligent Genetic Counseling,” Cooley Luw Review 3:175-191, 1985.

Doe v. University Hospital of the New York

University Medical Center, slip op. (N.Y Sup. Ct.,

7/31/90).

Drugan, A., Greb, A., Johnson, M. P., et al., ‘Determinants of Parental Decisions to Abort for Chromosome Abnormalities, “ Prenatal Diagnosis 10:483-

490, 1990.

Dumer v. St. Michael’s Hospital, 69 Wis. 2d 766,

233 N.W. 2d 372 (1975).
134 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

43,

44,

45<

46,

47.

48.

49,

50,

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

Edwar& v. United States, 519 F.2d 1137 (5th Cir.

1975).

Elias, S., Annas, G. J., and Simpson, J. L,, “Carrier

Screening for Cystic Fibrosis: Implications for

Obstetric and Gynecologic Practice,” American

Journal of Obstetrics and Gynecology 164:1077-

1083, 1991.

Elliot v. Brown, 361 So. 2d 546 (Ala. 1978).

Ellis v. Sherman, 512 Pa. 14,515 A.2d 1327 (1986).

Erlich, H. A., Roche Molecular Systems, Inc.,

Emeryville, CA, personal communication, September 1991.

Erlich, H. A,, Gelfand, D., and Sninsky, J. J., “Recent Advances in the Polymerase Chain Reaction, ’

Science 252:1643-1651, 1991.

Evans, R. M., “Report of the Council on Scientific

Affairs: Carrier Screening for Cystic Fibrosis,”

Proceedings of the American Medical Association

House of Delegates Annual Meeting, June 1991, pp.

330-337.

Faden, R. R., Chwalow, A. J., Quaid, K., et al.,

“Prenatal Screening and Pregnant Women’s Attitudes Toward the Abortion of Defective Fetuses, ”

American Journal of Public Health 77:288-290,

1987.

Faircloth v. Lamb-Grays Harbor Co., 467 F.2d 685

(5th Cir. 1972).

Favalora v. Aetna Casualty & Surety Co., 144 So.

2d 544 (La. App. 1962).

Fleisher, L. D., Sidley & Austin, Chicago, IL,

personal communication, September 1991.

Fost, N., University of Wisconsin School of Medicine, Madison, WI, remarks at U.S. Congress,

Office of Tmhnology Assessment workshop, ‘Cystic Fibrosis, Genetic Screening, and Insurance, ”

Feb. 1, 1991.

Fulton-Dekalb Hospital Authority v. Graves, 252

Ga. 441,314 S.E. 2d 653 (1984).

Funk, R. L., GeneScreen, Dallas, TX, personal

communication, March 1991.

Furrow, B. R., Widener University School of Law,

Wilmington, DE, personal communication, December 1991.

Gardner v. General Motors Corp., 507 F.2d 525

(lOth Cir. 1974).

Garrison v. Medical Center of Delaware, Inc., No.

193, 1988 (Sup. Ct. Del. 12/12/89).

Gellman, R. M., “Prescribing Privacy: The Uncertain Role of the Physician in Protecting Privacy, ”

North Carolina Luw Review 62:255-295, 1984.

GeneScreen, “Two Years Later . . . Seven Mutations in the CF Panel,” In the Cenome, Addendum,

summer 1991.

Golbus, M. S., Imughman, W. D., Epstein, C. J., et al.,

“Prenatal Diagnosis in 3,000 Amniocenteses, ”

63<

64,

65.

66,

67,

68,

69,

70.

71,

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

New England Journal of Medicine 300:157-163,

1979.

Gordon, H., “Genetic Counseling: Considerations

for Talking to Parents and Prospective Parents,”

Journal of the American Medical Association 217:

1215-1225, 1971.

German, C., ‘‘Can Drug Firms Be Trusted?,” Time

139:42-46, Feb. 10, 1992.

Greenstein, R. M., University of Connecticut Health

Center, Farmington, Cl’, personal communication,

February 1992.

Grody, W. W., “Status of the CAP Program in

Molecular Diagnosis, ” meeting abstract, Biotechnology and the Diagnosis of Genetic Disease:

Forum on the Tahnical, Regulato~, and Societal

Issues, Arlington, VA, Apr. 18-20, 1991.

Hague v. Williams, 37 N.J. 328, 181 A.2d 345

(1962).

Hammonds v. Aetna Casualty & Surety Co., 243 F.

Supp. 793 (N.D. Ohio 1966).

Harbeson v. Parke-Davis, 98 Wash. 2d. 460, 656

P.2d 483 (1983).

Havighurst, C. C., Duke University School of Law,

Durham, NC, personal communication, March 1992,

Helling v. Carey, 83 Wash. 2d 514, 519 P.2d 981

S. Ct. Wash. (1974).

Hillrnan, B. J., Joseph, C. A,, Mabry, M. R., et al.,

“Frequency and Costs of Diagnostic Imaging in

Office Practic~A Comparison of Self-Referring

and Radiologist-Referring Physicians, ’ New England Journal of Medicine 363:1604-1608, 1990.

Hilts, P. J., “U.S. Cracks Down on Health Devices

Made Before 1976,” New York Times, Feb. 24,

1992.

Hodel, M. B., ‘‘California Physician Says DNA Test

Kits Unreliable,” Associated Press, June 27, 1991.

Hoemke v. New York Blood Center, 912 F.2d 550

(2d Cir. 1990).

Holtzman, N. A., Johns Hopkins University Hospital, personal communication, December 1991.

Home v. Patton, 291 Ala. 701, 287 So. 2d 824

(1973).

Ingersoll, B., “Changes Vowed for Reviewing

Medical Devices: FDA Says It Will Improve Its

Regulation Program After Charges of Lapses,”

Wall Street Journal, Mar. 26, 1992.

Institute of Medicine, Medical Professional Liability and the Delivery of Obstetrical Care (Vol. I)

(Washington, DC: National Academy Press, 1989).

James G. v. Caserta, 332 S.E. 2d 872 (W.Va. 1985).

Kaplan, S., “Agency Door Revolves: As the FDA

Gets Going, Food-and-Drug Bar Gets Rich,’ Legal

Times, July 29, 1991, p. 1.

Kemmerlin v. Wingate, 274 S.C. 62,261 S.E. 2d 50

(1979).
Chapter S-Quality Assurance . 135

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

Kilshaw, D., “Quality Assurance. 1. Philosophy

and Basic Principles, ” Medical Laboratory Sciences 43:377-38 1, 1986.

Kilshaw, D., “Quality Assurance. 2. Internal Quality Control, ” Medical Laboratory Sciences 44:73-

83, 1987.

Kilshaw, D., “Quality Assurance. 3. External Quality Assessment, ’ Medical Laboratory Sciences

44:178-186, 1987.

King, P. A., “The Juridical Status of the Fetus: A

Proposal for the Legal Protection of the Unborn, ”

Michigan Luw Review 77:1647-1687, 1979.

Knoppers, B, M., University of Montreal School of

Law, Montreal, Canada, personal communication,

January 1992.

Kobrin, J. A., ‘‘Confidentiality of Genetic Information, University of Cal fornia--los Angeles Luw

Review 30:1283-1315, 1983.

Kolker, A., “Advances in Prenatal Diagnosis:

Social Psychological and Policy Issues, international Journal of Technology Assessment in Health

Care 5:601-617, 1989.

Lursen v. Yelle, 246 N.W. 2d 841 (Minn. 1976).

konard, C. O., Chase, G. A., and Childs, B., “Genetic Counseling: A Consumers’ View, ’ New

England Journal of Medicine 287:433-439, 1972.

Lininger v. Eisertbaum, 764 P.2d 1202 (CO1O.

1988).

Lippman-Hand, A., and Fraser, F. C., “Genetic

Counseling: Provision and Reception of Information, ’ American Jcwrna! of Medical Genetics

3:113-127, 1979.

Lippman-Hand, A., and Fraser, F. C., “Genetic

Counseling—The Post Counseling Period: I. Parents’ Perceptions of Uncertainty, ’ American Journal of Medical Genetics 4:51-71, 1979.

hngoria v. McAllen Methodist Hospital, 772 S.W.

2d 663 (Tex. App. 1989).

Lundahl v. Rock$cv-d Memorial Hospital Association, 93 Ill. App. 2d 461, 235 N.E. 2d 671 (1968).

MacDonald v. Clinger, 84 A.2d 482,444 N.YS. 2d

801 (1982).

Macri, J. N., Kasturi, R. V., Krantz, D. A., et al.,

“Maternal Serum Alpha-Fetoprotein Screening. II.

Pitfalls in Low-Volume Decentralized Laboratory

Performance, American Journal of Obstetrics and

Gynecology 156:533-534, 1987.

Matteson, K. J., “DNA Based Genetic Testing:

Current Proficiency Testing Activities, ” meeting

abstract, Biotechnology and the Diagnosis of Genetic Disease: Forum on the Technical, Regulatory,

and Societal Issues, Arlington, VA, Apr. 18-20,

1991.

Matteson, K. J., University of Tennessee Medical

Center-Knoxville, Knoxville, TN, personal communication, December 1991.

101.

102.

103.

104.

105.

106.

107.

108.

109,

110.

111.

112.

113.

114.

115.

116.

117,

118.

119.

120.

McCoid, A.H., “The Care Required of Medical

Practitioners,’ VanderbiltLuw Review 12:549-632,

1959,

Miller, S. R., and Schwartz, R.H., “Attitudes Toward Genetic Testing of Amish, Mennonite, and

Hutterite Families With Cystic Fibrosis, American

Journal of Public Health 82:236-242, 1992.

Moores v. Lucas, 405 So. 2d 1022 (F1. Dist. Ct. App.

1981).

Munro v. Regents of the University of Calt~ornia,

215 Cal. App. 3d 977,263 Cal. Rptr. 878 (1989).

Myers, J. E. B., “Abuse and Neglect of the Unborn:

Can the State Intervene?,” Duquesne Law Review

23:1-76, 1984.

Naccarato v. Grob, 384 Mich. 248 (1970).

National Institutes of Health, Workshop on Population Screening for the Cystic Fibrosis Gene,

“Statement From the National Institutes of Health

Workshop on Population Screening for the Cystic

Fibrosis Gene,’ New England Journal of Medicine

323:70-71, 1990.

National Intelligence Report 13(2), Oct. 28, 1991.

National Society of Genetic Counselors, “National

Society of Genetic Counselors Code of Ethics,”

Journal of Genetic Counseling 1:41-43, 1992.

Nationwide Mutual Insurance Co. v. Jackson, 10

Ohio App. 2d 137,226 N.E. 2d 760 (1967).

Naveed, M., Phadke, S. R., Sharrna, A., et al.,

‘‘Sociocultural Problems in Genetic Counseling,”

Journal of Medical Genetics 29:140, 1992.

Nelson v. Krusen, 678 S.W. 2d 918 (Tex. 1984).

Newman, S., “Privacy in Personal Medical Information: A Diagnosis, ’ University of Florida LUWI

Review 33:394-424, 1981.

Note, ‘‘Father and Mother Know Best: Defining the

Liability of Physicians for Inadequate Genetic

Counseling,’ Yale Law Journal 87:1488-1524,

1978.

Pearson, R. N., “The Role of Custom in Medical

Malpractice Cases, ‘‘ Indiana Luw Journal 51:528-

557, 1976.

Peninsula Counseling Center v. Rahm, 105 Wash.

2d 929,719 P.2d 926 (1986).

Phillips v, United States, 508 F, Supp. 537 (D.S.C.

1980).

Pitre v. Opelousas General Hospital, 530 So. 2d

1151 (La. 1988).

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Screening and Counseling for

Genetic Conditions: The Ethical, Social, and Legal

Implications of Genetic Screening, Counseling, and

Education Programs (Washington, DC: U.S. Government Printing Office, 1983).

Procanik by Procanik v. Cillon, 97 N.J. 339, 478

A.2d 755 (1984).
136 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

121.

122.

123.

124.

125,

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143,

Profitt v. Bartolo, 162 Mich. App. 35,412 N.W. 2d

232 (1987).

Prosser, W., and Keeton, W., “The Law of Torts,”

5th ed. (St. Paul, MN: West Publishing, 1984).

Rapp, R., “Chromosomes and Communication:

The Discourse of Genetic Counseling,” MedicaZ

Anthropology Quarterly 2:143-157, 1988.

Reilly, P., “Genetic Counseling and the Law,”

Houston Law Review 12%40-675, 1975.

Renslow v. Mennonite Hospital, 67 Ill. 2d 348, 10

Ill. WC. 484,367 N.E. 2d 1250 (1977).

I&&in, L., and Reilly, P., “Remedies for Improper

Disclosure by Genetic Data Banks,” RutgersCamden Luw Review 8:480-506, 1977.

Robertson, H. B., “Toward Rational Boundaries of

Tort Liability for Injury to the Unborn: Prenatal

Injuries, Preconception Injuries and Wrongful Life,’

Duke Law Journal 6:1401-1457, 1978.

Robertson, J. A., ‘‘bgal Issues in Genetic Testing, ’

The Genome, Ethics, and the L.uw: Issues in Genetic

Testing (Washington, DC: American Association

for the Advancement of Science, 1992).

Roe v. Wade, 410 U.S. 113 (1973).

Rosenstock, I. M., “The Evaluation of Genetic

Counseling: A Committee Report,” Public Health

Reporter 92:332-335, 1977.

Rothman, B. K., The Tentative Pregnancy (New

York, NY: Viking Penguin, 1986).

Rust v. Sullivan, 111 S. Ct. 1759 (1991).

Sanderson v. Bryan, 361 Pa. Super. 491,522 A.2d

1138 (1987).

Sandhoff, K., Conzelmann, E., Neufeld, E. F., et al.,

“The G~z Gangliosidoses, ” The Metabolic

Basis of Inherited Disease, C.R. Scriver, A.L.

Beaudet, W.S. Sly, et al., (eds.) (New York,

NY: McGraw Hill, 1989).

Schork v. Huber, 648 S.W. 2d 861 (Ky. 1983).

Schroeder v. Perkel, 87 N.J. 53, 432A A.2d 834

(1981).

Shiloh, S., and Sagi, M., ‘‘Effect of Framing on the

Perception of Genetic Recurrence Risks,” American Journal ofikledical Genetics 33:130-135, 1989.

Siemieniec v. Lutheran General Hospital, 117 Ill.

2d 230, 111 Ill. Dec. 302,512 N.E. 2d 691 (1987).

Simonson v. Swenson, 104 Neb. 224, 177 N.W. 831

(1920),

Singer, E., “Public Attitudes Toward Genetic

Testing,” Population Research and Policy Review

10:235-255, 1991.

Smith v. Cote, 128 N.H. 231,513 A.2d 341 (1986).

Sorenson, J.R., Swazey, J. P., and Scotch, N.A.,

Reproductive Pasts, Reproductive Futures: Genetic

Counseling and Its Effectiveness (New York, NY:

Alan R. Liss, Inc., 1981).

Starr, P., The Social Transformation of Medicine

(New Yorlq NY: Basic Books, 1982).

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

Strickland, D.M., Butzin, C.A., and Wians, F.H., Jr.,

“Maternal Serum Alpha-Fetoprotein Screening:

Further Consideration of kw-Volume Testing,”

American Journal of Obstetrics and Gynecology

164:711-714, 1991.

Swee, D.E., and Micek-Galinat, L., “Part I: Basic

Approach to Health Screening,” New Jersey Mech”-

cine 88:421-426, 1991.

Tarasoff v. Regents of the Um”versity of California,

17 Cal. 3d 425131 Cal. Rptr. 14,551 P.2d 334,83

A.L.R. 3d 1166 (1976).

The TJ. Hooper, 60 F.3d 737 (2d Cir. 1932).

Tirone, A.J., Ofllce of Survey and Certification,

Health Standards, and Quality Bureau, Health Care

Financing Administration, letter to M.S. Watson,

Cytogenetics Laboratory, St. Louis Children’s Hospital, Oct. 24, 1991.

Toth v. Community Hospital at Glen Cove, 22 N.Y

2d 255,292 N.Y3. 2d 440,239 N.E.2d 368 (1968).

Truman v. Thomas, 27 Cal. 3d 285, 165 Cal. Rptr.

308,611 P.2d 902 (S.C. Cal. 1980)

Turpin v. Sortini, 31 Cal. 3d 220,182 Cal. Rptr. 337,

643 P.2d 954 (1982).

U.S. Congress, General Accounting Office, FederaZ

Regulation of Medical Device&roblems Still To

Be Overcome, GAO/HRD-83-53 (Gaithersburg,

MD: General Accounting Office, September 1983).

U.S. Congress, General Accounting Office, it4edicaZ

Devices: Early Warning of Problems is Hampered

by Severe Underreporting, GAO/PEMD-87-l

(Gaithersburg, MD: U.S. General Accounting Office, December 1986).

U.S. Congress, General Accounting Office, A4edicaZ

Devices: Early Warning of Problems is Hampered

by Severe Unahreporting, Statement of Eleanor

Chelimsky, Assistant Comptroller General, GAO/

PEMD-87+ (Gaithersburg, MD: U.S. General Accounting Office, May 1987).

U.S. Congress, General Accounting Office, Medical

Devices: FDA’s Forecasts of Problem Reports and

FTEs UnderH.R. 4640, GAO/PEMD-88-30 (Gaithersburg, MD: U.S. General Accounting Office, July

1988).

U.S. Congress, General Accounting Office, MedicaZ

Devices: FDA’s 501(k) Operations Could Be Improved, GAO/PEMD-88-14 (Gaithersburg, MD:

U.S. General Accounting Office, August 1988).

U.S. Congress, General Accounting Office, A4edicaZ

Devices: FDA’s Implementation of the Medical

Device Reporting Regulation, GAO/PEMD-89-10

(Gaithersburg, MD: U.S. General Accounting Office, February 1989).

U.S. Congress, General Accounting Office, Medical

Device Recalls: An Overview andAnalysis 1983-88,

GAO/PEMD-89-15BR (Gaithersburg, MD: U.S.

General Accounting Office, August 1989).
Chapter S--Quality Assurance ● 137

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

U.S. Congress, General Accounting Office, FDA

Resources: Comprehensive Assessment of Staffing,

Facilities, and Equipment Needed, GAO/HRD-89-

142 (Gaithersburg, MD: U.S. General Accounting

Office, September 1989).

U.S. Congress, General Accounting Office, Medical

Device Recalls: Examination of Selected Cases,

GAO/PEMD-90-6 (Gaithersburg, MD: U.S. General Accounting Office, October 1989).

U.S. Congress, General Accounting Office, Medical

Devices: The Public Health at Risk, statement of

Charles Bowsher, CornptmllerGtmral, GAOfl-PEMD90-2 (Gaithersburg, MD: U.S. General Accounting

Office, November 1989).

U.S. Congress, General Accounting Office, Medical

De~’ices: Underreporting of Problems, Backlogged

Systems, and Weak Statutory Support, Statement of

Eleanor Chelimsky, Assistant Comptroller General,

GAO/T-PEMD-90-3 (Gaithersburg, MD: U.S. General Accounting Office, November 1989).

U.S. Congress, General Accounting Office, Medical

Technology: Quality Assurance Needs Stronger

Management Emphasis and Higher Priority, GAOI

PEMD-92-1O (Gaithersburg, MD: U.S. General

Accounting Office, February 1992).

U.S. Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on

Health and the Environment, Health and the Environment Miscellaneous, Part 2, O~~ersight Hearing

on the Medical Device Amendments of 1976,

hearing Feb. 24, 1984, serial No. 98-108 (Washington, DC, U.S. Government Printing Office, 1984).

U.S. Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on

Oversight and Investigations, FDA Oversight: Medical De\’ices, hearing July 16, 1982, serial No.

97-144 (Washington, DC: U.S. Government Printing Office, 1982).

U.S. Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on

Oversight and Investigations, Medical Device Regulation. The FDA Neglected Child, Committee

Print 98-F (Washington, DC: U.S. Government

Printing Office, May 1983).

U.S Congress, House of Representatives, Committee on Energy and Commerce, Subcommittee on

Oversight and Investigations, “CLIA Oversight,”

hearing, May 2, 1991.

U.S. Congress, Office of Technology Assessment,

Federal Policies and the Medical De~ices Industry,

OTA-H-229 (Springfield, VA: National Technical

Information Service, October 1984).

U.S. Congress, Office of Technology Assessment,

Genetic Witness: Forensic Uses of DNA Tests,

OTA-BA-438 (Washington, DC: U.S. Government

Printing Office, July 1990).

170.

171.

172.

173.

174,

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and Genetic Screening: Policies,

Practices, and Attitudes of Genetic Counselors—

Results of a Survey, OTA-BP-BA-97 (Washington,

DC: U.S. Government Printing Office, forthcoming

1992),

U.S. Congress, Office of Technology Assessment,

Defensive Medicine and the Use of Medical Technology, forthcoming 1993.

U.S. Congress, Office of Technology Assessment,

Technolog3~, Insurance, and the Health Care System, forthcoming 1993.

United States ex rel Fear v. Rundle, 506 F.2d 331

(3rd Cir. 1974), cert. denied 421 U.S. 1012 (1975).

Valverde, K. D., The Cystic Fibrosis Center, St.

Vincent’s Hospital and Medical Center, New York

NY, personal communication, February 1992.

Viccaro v. Milunsky, 406 Mass. 777,551 N.E. 2d 8

(Mar. 1, 1990).

Vlek, C., “Risk Assessment, Risk Perception and

Decision Making About Courses of Action Involving Genetic Risk: An Overview of Concepts and

Methods, ’ Decision Making Under Uncertainty, R.

Scholz (cd.) (Amsterdam, The Netherlands: North

Holland Publishing Co., 1983).

Walker v. Mart, 790 P.2d 735 (1990).

Wang, V., and Marsh, F. H., “Ethical Principles and

Cultural Integrity in Health Care Delivery: Asian

Ethnocultural Perspectives in Genetic Services, ”

Journal of Genetic Counseling 1:81-92, 1992.

Weil, J., “Mothers’ Postcounseling Beliefs About

the Causes of Their Children’s Genetic Disorders, ’

American Journal of Human Genetics 48:145-153,

1991.

Wertz, D. C., Fletcher, J. C., and Mulvihill, J. J.,

“Medical Geneticists Confront Ethical Ddemmas:

Cross-Cultural Comparisons Among 18 Nations,”

American Journal of Human Genetics 45:1200-

1213, 1990.

Wertz, D. C., Janes, S. R., Rosenfield, J. M., et al.,

‘‘Attitudes Toward the Prenatal Diagnosis of Cystic

Fibrosis in Decision Making Among Affected

Families, American Journal of Human Genetics

50:1077-1085, 1992.

Wertz, D. C., Rosenfield, J. M., Janes, S. R., et al.,

“Attitudes Toward Abortion Among Parents of

Children With Cystic Fibrosis, ” American Journal

of Public Health 81 :922-996, 1991.

Wertz, D. C., Sorenson, J. R., and Heeren, T. C.,

“Genetic Counseling and Reproductive Uncertainty, ” American Journal of Medical Genetics

18:79-88, 1984.

Willey, A. M., ‘‘Genetics Laboratory Quality Assurance-Overview, meeting abstract, Biotechnology and the Diagnosis of Genetic Disease: Forum
138 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

185.

186.

187.

188.

on the Technical, Regulatory, and Societal Issues, 189. Yoder, F., U.S. Food and Drug Adrninistration,

Arlington, VA, Apr. 18-20, 1991. Rockville, MD, remarks at the 8th International

Willey, A. M., New York State Department of Congress of Human Genetics, Washington, DC,

Health, Albany, NY, personal communication, Jan- October 1991.

Uary 1992.

Wilson v. Kuenzi, 751 S.W. 2d 741 (Me. 1988). 190. Yoder, F., U.S. Food and Drug Administration,

Winslade, W. J., “Confidentiality of Medical Re- Rockville, MD, personal communication, February

cords, ’ Journal of Legal Medicine 3:497-533,

1982.

1992.

Wolf, E. L,, “Blood Collector Liability and the

Professional Standard of Care,” Courts, Health

Science & the Luw 2:184-188, 1991.
Chapter 6

Education and Counseling
Contents

Page

THE NEED FOR SUFFICIENT AND APPROPRIATE EDUCATION

AND COUNSELING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Pretest Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Understanding Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

THE SCENARIO FOR CYSTIC FIBROSIS COUNSELING . . . . . . . . . . . . . . . . . . . . . . . 145

A Priori Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Testing To Determine Risks for Relatives of Affected Individuals . . . . . . . . . . . . . . . . . 145

Screening To Determine Risks of Those With No Family History . . . . . . . . . . . . . . . . . 146

Prenatal Diagnosis of Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147

Informing Relatives and Inductive Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

Post-Test Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

The Need for Better Public Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

STRATEGIES FOR SCREENING VARIOUS POPULATIONS . . . . . . . . . . . . . . . . . . . . 150

Newborn Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Adolescent Preconceptional Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

Adults—Preconceptional or Prenatal? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

PROFESSIONAL CAPACITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

Master’ s-Level Counselors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

Non-Master’ s-Level Counselors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

Other Health Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

THE FEDERAL ROLE IN DECIDING THESE ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

NIH Clinical Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

Funding for Genetic Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

RESULTS OF NONFEDERAL PILOTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160

Baylor College of Medicine: Prenatal and Preconceptional Carrier Screening

of Couples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Cornell University Medical College: Prenatal Carrier Screening . . . . . . . . . . . . . . . . . . . 161

Genetics & IVF Institute: Elective Fetal Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Roche Biomedical Laboratories: Prenatal Couples Screening . . . . . . . . . . . . . . . . . . . . . 162

McGill University: High School Carrier Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

Permanence Medical Group, Inc.-Vivigen-Integrated Genetics:

Carrier Screening of Pregnant Women - —

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

CHAPTER 6 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Boxes

6-A. Maternal Serum Alpha-Fetorotein Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

6-B. Clinical Studies of Testing, Education, and Counseling for Cystic Fibrosis

Mutations, National Institutes of Health ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

Figures

6-1. Decisionmaking in Premarital Carrier Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

6-2. Federal Support of Genetic Services Through the Special Projects of

Regional and National Significance (SPRANS), 1978-91 . . . . . . . . . . . . . . . . . . . . . . . 160

Tables

6-1. A priori Carrier Risks for Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

6-2. Adjusted Carrier Risks After Negative est Results at Various Detection Rates . . . 146

6-3. Potential for Detecting Couples at Risk for a Child With Cystic Fibrosis . . . . . . . . . 146

6-4. Cystic Fibrosis-Related Risks After Mutation Analysis for Carrier Status . . . . . . . . 147

6-5. Total Funding for Genetic Services by State, Fiscal Year 1990 . . . . . . . . . . . . . . . . . . 159

6-6. Funding for Genetics Education, Technical Assistance, and Training . . . . . . . . . . . . . 160
Chapter 6

Education and Counseling

Major questions raised by the implementation of

routine CF carrier screening include:

Can pretest education and post-test counseling

adequately inform participants and prevent

harm?

What is the role of public education as a source

of pretest information?

Who should be offered screening and in what

setting?

Can confidentiality be assured?

Is quality assurance possible?

The answers to these questions will surface as

time passes and the results of several pilot projects

in the United Kingdom (ch. 10) and the United States

become available. How education for cystic fibrosis

(CF) carrier screening is conducted will likely serve

as a prototype for screening for other autosomal

recessive disorders. This chapter examines the

educational and counseling issues that will need

addressing as CF carrier screening becomes more

widespread, as well as the roles of various health

professionals.

There are no mandatory genetic screening programs of adult populations in the United States. In

this regard, OTA finds it highly unlikely that CF

carrier screening will set a precedent. In a 1991 OTA

survey of 431 genetic counselors and nurses in

genetics, 99 percent of those who responded said CF

carrier screening should be voluntary (71). Thus, this

chapter assumes voluntary screening and examines

factors in delivering CF carrier screening to a large 

group of Americans. Topics discussed are: the

complexity of pretest education and post-test counseling for CF carrier status; the capacity of the

professional clinical genetics community to assume

the primary role in the provision of counseling; the

most appropriate sites, facilities, and resources for

screening; and contributions to be made by CF

carrier screening pilot projects.

THE NEED FOR SUFFICIENT AND

APPROPRIATE EDUCATION AND

COUNSELING

For some individuals, even considering whether

to undergo genetic screening or testing constitutes a

potential life crisis because of the possible outcomes. If the results are positive, the crisis is

exacerbated. How results affect an individual has

much to do with the person’s own frame of

reference, but also with the implications of the

condition and its prognosis.

Psychological issues permeate every aspect of

genetic consultation. Information received can be

ego-threatening, or even life-threatening, as individuals find they are ‘‘ flawed,’ ‘‘imperfect, ’ ‘ ‘defective.’ ‘‘inadequate, ’ or ‘‘abnormal, ’ and could

potentially transmit these “flaws” to their progeny

(37). How the information is obtained, communicated, retained, and eventually used by the person

being tested or screened involves a “series of

complex, multidimensional processes with major

rational and nonrational components” (37).

Beyond the intrapsychic consequences of receiving genetic information are the potential impacts on

family. Genetic information affects not only the

individual, but also the partner, parents, grandparents, siblings, and children of the individual being

tested or screened. Social and psychological stress,

as well as future financial and emotional burdens,

can strain family functioning (61).

The psychological impact of a positive diagnosis

varies with its severity, treatability, and potential for

different families to react uniquely to similar situations. Support, counseling, and followup can assist

individuals and their families in coping with positive

test results. The knowledge and skills of a properly

trained counselor can help the individual understand

the diagnosis, risk, prognosis, and relevant preventive and therapeutic measures, and also aid in

communicating important information to other family members. When these goals are accomplished,

genetic counseling is usually perceived as a valuable

experience by the counselee and the professional

(50).

Pretest Education

In routine genetic counseling, the genetics professional elicits the reasons for testing or screening and

discusses the implications of possible outcomes.

The counselor prepares the individual for both

positive and negative test results. It is also the time

–141–
142 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

IT’S YOUR

CHOICE

Photo credit: Peter T. Rowley,

University of Rochester School of Medicine

Educational materials, such as this pamphlet developed at

the University of Rochester School of Medicine, Rochester,

NY, can be useful for pretest education.

to discuss risk reduction strategies, if relevant, and

the nature and severity of the disorder for which the

test is being done. Counseling for CF carrier

screening, if conducted in the typical genetic services setting, is no different from routine counseling

for other disorders for which tests have less-thanperfect sensitivity.

Most studies of genetic counseling have focused

on cases where the client already has an affected

child or relative and is familiar with the disorder.

Experience with Tay-Sachs, sickle cell anemia, and

ß-thalassemia screening provides some information

about the effects of education prior to screening

people with no previous family history of the

condition for which they are being screened (app. B).

Clearly, without pretest education—and in some

cases even after such education—misperceptions

can be great. Pretest education is imperative in

cases where there has been no family history-i. e.,

screening.

Understanding Risk

One task of the genetics professional is to

communicate risks to the client-a job not easily

performed (31). A decision to be screened or tested

will be influenced by a person’s perception of the

chance that the test will be positive, The interpretation

●

●

●

●

●

of numerical risk varies depending on:

prior perception of the magnitude of the risk,

anxiety of the client at time of test,

familiarity with the outcome (whether there is

an affected relative or fiend),

how treatable the condition is, and

belief that the outcome with which the individual is familiar is representative of all such

outcomes (34).

Cultural differences need to be understood, as they

also influence interpretation of risk (46).

The perception of risk is a more important

determinant of decisionmaking than the actual risk.

The way risks are posed can influence the client’s

choices. When confronted with the risk of genetic

disease in their offspring and when making reproductive decisions, people tend to place greater

weight on their ability to cope with a disabled or

fatally ill child than on precise numerical risks. For

some couples, for example, a risk of 10 percent could

be perceived no differently from a risk of 50 percent

if they believe that they cannot cope with the

situation. In prenatal counseling, regardless of actual

risk, parents might perceive the chance of occurrence as either O or 100 percent-it either will or will
Chapter 6---Education and Counseling ● 143

not happen. By processing risks in this way,

individuals simplify probabilistic information and

shift their focus to the implications of being at risk

and the potential impact of what could occur (40).

In addition to subjective factors that influence the

interpretation of risk, many individuals have difficulty understanding risk in arithmetic terms. Comprehension of the concepts of probability and risk

influence a clients understanding of the information

provided by genetic tests. In a Maryland study of 190

predominantly Caucasian, middle-class women,

over one-fifth thought that ‘‘1 out of 1,000’ meant

10 percent, and 6 percent thought it meant greater

than 10 percent (12). In addition, interpretation of

risks varies according to whether they are presented

as a single figure or in comparison to a variety of

genetic risks (65).

Even for individuals who are familiar with a

disease because they have an affected family member, comprehending risks can be elusive. In a study

of 190 subjects from 100 families with a family

member with adult polycystic kidney disease (APKD)

—a kidney disease inherited in an autosomal dominant fashion (each child of an affected individual has

a 50 percent chance of inheriting the disease)---most

tested poorly on questions reflecting their knowledge of the genetics of APKD. Twenty-nine percent

had a genetic knowledge score considered good or

excellent, while 46 percent had poor or absent

knowledge (30).

How risks are framed also influences understanding and choices (45). Deciding to have a genetic test

can be different if the risk is presented as a 25 percent

chance of having an affected child rather than a 75

percent chance of having an unaffected child (31).

Risk perceptions vary among individuals and among

counselees and counselors: Patients tend to interpret

the same level of numerical risk as lower than do

geneticists (79).

Presenting risks in personal terms can improve the

chance that the information will be understood. For

example, one genetics center that conducts routine

carrier screening for hemoglobinopathies in at-risk

populations uses a videotaped drama to present

information about screening during pregnancy and

has demonstrated effective and lasting transmission

of information (41). Videos of patients are particularly useful in demonstrating the gestalt of a

condition, its natural history at various ages, and

variability among affected individuals (4).

A recent survey of public attitudes regarding

genetic tests revealed that belief in the technology’s

accuracy is one of the strongest predictors of

favorable attitudes toward its use (66). Thus, an

individual’s decision to undergo screening or testing

is likely influenced by the manner in which the

accuracy of the test is presented. Even under the best

circumstances, however, counseling might not be

satisfactory. In a survey of 1,369 counseling cases at

47 clinics-after counseling sessions that typically

lasted 45 to 60 minutes—both the counselor and the

patient were aware of what topic the other party had

most wanted to discuss in only 26 percent of the

sessions. In almost half the sessions, neither party

ever became aware of what the other had most

wanted to discuss (80). Many of the undesirable

psychological effects of screening might be avoided

or reduced by careful attention to patients’ needs at

each stage of the screening process.

Maternal serum alpha-fetoprotein (MSAFP) screening is instructive in this regard. Women who are

notified that their MSAFP test is abnormally low or

high must await further testing, either through

ultrasound or amniocentesis, to rule out the possibility of a fetus with Down syndrome or a neural tube

defect, but a small percentage of neural tube defects

will still be missed (box 6-A). (This situation

parallels that of a pregnant woman who finds she is

a carrier for CF and must sometimes await the results

of her partner’s test and subsequent fetal tests.) The

mental anguish and apprehension that women encounter when faced with the prospect of having a

child with a condition such as Down Syndrome is

well documented (20,69). Although increased anxiety among women might persist until a definite

chromosomal diagnosis by amniocentesis rules out

the condition, initial anxiety can be reduced by

comprehensive genetic counseling (36).

The importance of informed consent, careful

presentation of counseling, and confidentiality have

long been recognized as essential components of

genetic testing and screening (29). Geneticists,

perhaps more than any other medical specialists,

have advocated a nondirective approach to counseling and have a strong commitment to patient

autonomy (6). Further, a history of concern exists

about genetic information being delivered by health

professionals used to a more directive approach (13).

This concern has been played out in the debate over

MSAFP and is a factor in the reluctance of the

clinical genetics community to rush toward wide-
144 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 6-A—Maternal Serum Alpha-Fetoprotein Screening

Alpha-fetoprotein (AFP) is a glycoprotein that is synthesized first by the embryonic yolk sac and later by the

fetal gastrointestinal tract and liver. Its concentration in fetal serum is 150 times that found in amniotic fluid; an even

smaller amount enters maternal blood, most likely through the placenta. Although its function in the fetus is unclear,

the association of an abnormally increased AFP concentration in maternal serum with a variety of fetal abnormalities

and adverse pregnancy outcomes has been known for 20 years. Elevated maternal serum AFP (MSAFP) can indicate

an open neural tube defect (NTD) or an abdominal wall defect in the fetus. Abnormally low MSAFP levels are

associated with fetal chromosomal abnormalities such as Down syndrome.

As with some other screening tests, the incidence of false positive MSAFP tests is high, and about 4 to 5 percent

of women have abnormally high initial MSAFP values. More than half these women will have abnormal results

when tests are repeated and will need to be assessed by ultrasonography. Because MSAFP levels must be correlated

precisely with gestational age and the number of fetuses, ultrasonography provides an explanation for the elevated

MSAFP in about half these women because of either incorrect dating of the last menstrual period or multifetal

gestation. Thus, 1 to 2 percent of all women screened will be candidates for diagnostic amniocentesis to assess the

AFP concentration of their amniotic fluid, and about 1 in 10 will ultimately be found to have a fetus with a NTD.

At the other end of the curve, another 5 percent of all women screened will have abnormally low MSAFP.

Ultrasound eliminates half of these women from further evaluation because of inaccurate gestational dating, and

the other half will be advised to undergo amniocentesis for karyotyping; 1 in 40 will have a chromosomally

abnormal fetus.

Because of the number of false results at both ends of MSAFP screening, the cost-effectiveness of universal

screening was debated widely during the early years of the assay’s development. Moreover, there was heightened

concern about the possibility that the test could fall into the hands of practitioners not familiar with the complexities

of the required followup. Of further concern was the reproducibility of results with the available assay kits, as well

as the lack of standardized controls for the specific population studies. In 1978, the U.S. Food and Drug

Administration (FDA) was on the verge of releasing AFP test kit reagents on a totally unrestricted basis. The

American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP)

formed a task force on the issue that concluded:

There is no precedent in the United States for a mass disease detection program that requires the coordination

of so many disparate elements of the health care system as in APP screening. Maternal serum AFP screening should

be implemented initially only where it can be done within a coordinated system of care which contains the requisite

resources and facilities to provide proper safeguards and potential for follow through.

AAP and the American Society of Human Genetics (ASHG) asked FDA to restrict MSAFP testing to programs

that can provide qualified personnel and equipment, rather than making the test available to every pregnant woman

regardless of capability for followup. In 1983, the FDA adopted unrestricted regulations approving MSAFP test kits,

making expanded use of the test possible.

A properly designed MSAFP program demands public education, assurance of quality laboratory work

accurate interpretation of test results, and public health tracking to assure appropriate followup and testing of

positive results. Misinterpretation or improper followup could result in either the unwanted birth of a seriously

impaired child or the termination of a healthy fetus. MSAFP screening also depends on the availability of ancillary

services (counseling, ultrasound, amniocentesis) for further diagnostic evaluation, particularly in underserved areas.

At the time the test kit was introduced, there was concern that sufficiently equipped facilities and trained personnel

were not yet available to handle the large number of potential cases.

In 1986, ACOG recommended to physicians that MSAFP screening be offered to all women, and, at least

legally, such screening became the de facto standard of care. In the same year, ASHG developed a policy statement

detailing the conditions necessary to provide for appropriate use of this test. Today, numerous MSAFP screening

programs operate in the United States. By its very nature, MSAFP screening is the kind of program that lends itself

to a State or regional public health approach since there is no clearly definable high-risk group. It is standard practice

to refer women with positive test results to specialized diagnostic centers for confirmation. It is unclear, however,

whether the counseling needs of this high-anxiety group are being met.

SOURCE: Office of Technology Assessment, based on G.C. Cunningham and L.C. Gilstrap, “Maternal Serum Alpha-Fetoprotein Screening,”

New England Journal of Medicine 325:55-57, 1991; and G.C. Cunningham and K.W. Kizer, ‘‘Maternal Serum Alpha-Fetoprotein

Screening Activities of State Health Agencies: A Survey, “ American Journal of Human Genetics 47:899-903, 1990.
Chapter Education and Counseling ● 145

spread screening for any disease. Nearly 82 percent

of the respondents surveyed by OTA said the human

genetics community should be the primary organizer

of CF carrier screening programs. Also mentioned

were State or local health departments (59 percent)

and primary care givers (27 percent). Over 89

percent felt CF population screening should be

provided in genetics centers, but 59 percent felt that

carrier screening could also be provided in the

primary care setting or organized, community-wide

programs (54 percent). Concern about the sometimes difficult nature of communicating risk information regarding CF (as described in the following

section)---even for experienced genetic centers—

has led some in the clinical genetics community to

warn against rapid movement to routine CF carrier

screening (5).

THE SCENARIO FOR CYSTIC

FIBROSIS COUNSELING

As mentioned earlier, while the CF mutation

assay poses probabilistic uncertainties, similar circumstances exist for other tests, such as MSAFP.

Education and counseling for CF carrier screening

need not be viewed in a vacuum.

OTA’s survey found genetic counselors and

nurses in genetics estimate that, on average, 1 hour

is needed to obtain a three-generational family

history and to discuss carrier assays and recurrence

risks, regardless of family history (71). The majority

(70 percent) of genetic counselors and nurses in

genetics surveyed by OTA feel that widespread

screening should be withheld until a sensitivity of 95

percent or more is attained (71). This section focuses

on some common scenarios likely to be encountered

in routine CF carrier screening.

A Priori Risks

Before providing DNA analysis for CF carrier

status, it is important to understand and explain to

the client his or her a priori risk-that is, an

individual’s risk prior to any test result. Two factors

significantly influence an individual’s a priori risk of

being a CF carrier: ethnicity and presence or absence

of a family history of CF. In the case of a positive

history, an individual’s chance of being a carrier

depends on his or her relationship to the individual

with CF. With a negative family history for CF, an

individual’s ethnic background is most important in

defining a priori risk. Table 6-1 presents the a priori

Table 6-l—A Priori Carrier Risks for Cystic Fibrosis

Negative family history

Caucasian. . . . . . . . . . . . . . . . . . . . 1 in 25 (4%)

African American. . . . . . . . . . . . . . . 1 in 60 to 65 (1.5 to 1.7%)

Asian American. . . . . . . . . . . . . . . . 1 in 150 (0.7%)

Hispanic American, . . . . . . . . . ., . 1 in 46 (2.2%)

Positive family history

Parent of child with CF. . . . . . . . . . 1 in 1 (1 OOO/.)

Sibling with CF. . . . . . . . . . . . . . . . 2 in 3 (670/f)

Aunt or uncle with CFa. . . . . . . . . . 1 in 3 (33°/0)

First cousin with CF. . . . . . . . . . . . . 1 in 4 (25%)

Niece/nephew with CFa. . . . . . . . . 1 in 2 (50%)

a Consanguineous.

SOURCE: Office of Technology Assessment, 1992.

probabilities of carrier status for individuals with

negative and positive family histories of CF.

Prior to any CF carrier screening, patient prescreening education is imperative. It is important potential

screenees understand information regarding a priori

risk, types of tests available, and uncertainties in risk

assessment based on screening results.

Testing To Determine Risks for Relatives of

Affected Individuals

Currently, it is accepted practice to offer CF

carrier tests to individuals who have a positive

family history of CF (71). OTA’s survey of genetic

counselors and nurses revealed 86 percent of respondents’ clinics have policies stating CF carrier tests

should be routinely offered to individuals with a

positive family history of CF but not to those with a

negative family history.

OTA’s finding that clinics’ policies offer CF

carrier assays to those with positive family histories

is not surprising. An unaffected sibling of an

individual with CF has a 2 in 3 likelihood of being

a CF carrier. A consanguineous uncle or aunt of an

individual with CF has a 1 in 2 likelihood of being

a carrier. A first cousin of an individual with CF has

a 1 in 4 likelihood of being a carrier (table 6-l).

In families where CF is due to the DF508 or

another common mutation, carrier tests are relatively straightforward. If an undescribed CF mutation is involved, however, carrier detection might

not be possible via direct mutational analysis. In

these cases, indirect methods must be used, and there

is a possibility that several family members will

require analysis to arrive at an answer regarding

carrier status. For at-risk families (those with a

consanguineous relative who has or had CF), the use
146 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 6-2—Adjusted Carrier Risks After Negative

Test Results at Various Detection Rates

Table 6-3-Potential for Detecting Couples at Risk

for a Child With Cystic Fibrosis

Percent detection

Relationship 75 80 85 90 95

of affected a priori

consanguineous.

SOURCE: Office of Technology Assessment, 1992.

of restriction fragment length polymorphism analysis in conjunction with direct detection of DF508 and

other CF mutations can improve the tests’ sensitivity

to nearly 100 percent (ch. 4). The individual whose

test reveals a CF mutation is definitely a carrier (the

test is 100 percent predictive). However, if no

mutation is found (a negative test), carrier status

cannot be ruled out. Thus, CF tests, at best, can

provide a definitive positive answer. At worst, they

alter or modify the assessment of individuals’ or

couples’ risk from their a priori risk. CF mutation

analysis does not alter the actual risk, it merely

reduces the uncertainty about what that actual risk is.

CF mutation analysis can adjust the assessment of

risk downward: Table 6-2 displays how those risks

are adjusted after analysis at several test sensitivities. As the sensitivity improves, the uncertainty—

i.e., possibility of a false negative result-diminishes. For example, without any testing, a sibling of

an individual with CF has an a priori risk of 2 in 3,

or 67 percent, of being a carrier. If the sibling is

tested for CF carrier status using a test that is 85

percent sensitive and is found to be negative, the

adjusted risk of being a carrier is 23 percent. At 90

percent sensitivity, the carrier risk drops to 17

percent.

Screening To Determine Risks of Those With

No Family History

To date, most genetic counselors do not offer

unsolicited CF mutation assays to individuals with

a negative family history (71). The American

Society of Human Genetics (ASHG) and a workshop

of the National Institutes of Health (NIH) published

policy documents in 1990 discouraging CF carrier

screening (1 1,53); a 1992 ASHG statement reaffims

Percent of cystic fibrosis

mutations detectable Percent of carrier couples detectable

75 56.3

85 72.3

90 81.0

95 90.3

SOURCE: W.K. Lemna, G.L. Feldman, B.-S. Kerem, et al., “Mutation

Analysis for Heterozygote Detection and the Prenatal Diagnosis

of Cystic Fibrosis,” New England Journal of Medicine 322:291 -

296, 1990.

that position (50). OTA’s survey found 21 percent of

respondents felt that CF carrier tests should be

offered to individuals with no family history of CF.

CF mutation analysis can, however, yield information about the carrier status or risk for individuals

who have no family history of CF. In the recent past,

the sensitivity of the carrier test was limited to the

frequency of the DF508 mutation. Today, however,

most commercial and university laboratories examine DF508 and 6 to 12 additional mutations. Taken

together, these mutations comprise 85 to 90 percent

of CF mutations in U.S. Caucasians (95 percent in

Ashkenazic Jews). Counselors report an almost even

split between commercial and university-based laboratories as the facility performing their CF mutation assays (45 percent and 48 percent, respectively)

(71).

As with individuals who have affected relatives,

determining risks in persons with no family history

of CF also depends on test sensitivity. At 85 percent

test sensitivity, about 72 percent (0.85 x 0.85) of

at-risk couples will be identified. As the sensitivity

of the assay improves, a greater proportion of +/+

couples can be identified (table 6-3). Simlarly, at 85

percent sensitivity, the probability that a couple

from the general population would bear a child with

CF is reduced from 1 in 2,500 to about 1 in 16,100

if one partner is screened and found to be negative;

risk is reduced to 1 in 103,700 if both have negative

test results. In roughly 7 percent of couples screened

for CF mutations, one partner will be found to carry

a mutation and the other will not (+/-). Such couples

constitute the most difficult counseling situation

because, assuming 85 to 90 percent sensitivity, the

risk of having an affected child remains 1 in 644

(table 6-4). Computerized programs have been

developed to incorporate factors such as a priori risk

and mutation frequency when determining risk. In

addition, a “slash sheet, ’ or pedigree flow chart,
Chapter 6--Education and CounselingŽ . 147

Table 6-4--Cystic Fibrosis-Related Risks After Mutation Analysis for Carrier Statusa

Risk of cystic fibrosis in offspring

Percent of cystic One parent

fibrosis mutations Carrier risk for person One screened; positive, one Both parents

detectable with negative test negative result parent negative negative

o 1 in 25 1 in 2,500 N A

b

1 in 2,500

75 1 in 97 1 in 9,700 1 in 388 1 in 37,600

85 1 in 161 1 in 16,100 1 in 644 1 in 103,700

90 1 in 241 1 in 24,100 1 in 964 1 in 232,300

95 1 in 481 1 in 48,100 1 in 1,924 1 in 925,400

a Assumes earner frequency of 1 in 25.

b NA = Not applicable.

was developed to assist in the estimation of risk (21).

The value of either of these tools in the clinical

setting is yet to be determined.

Prenatal Diagnosis of Cystic Fibrosis

In addition to CF carrier screening of adults,

prenatal diagnosis of CF can be performed. The type

of test used to establish carrier status of the parents

determines the DNA protocol for the fetus. The

choice of technique to obtain a sample for DNA

analysis involves consideration of timing, procedural risk, access to procedures, cost, and the

presence or absence of other indications for prenatal

diagnosis. Cells can be obtained via chorionic villus

sampling (CVS) (performed at 9 to 12 weeks of

pregnancy), amniocentesis (performed at 16 to 18

weeks), or through percutaneous umbilical blood

sampling, also called cordocentesis (performed at 20

weeks). When CF mutation analysis is unavailable

or inconclusive, microvillar intestinal enzyme levels

can sometimes be measured in the amniotic fluid at

17 to 18 weeks, but this method suffers from a high

false-positive and false-negative rate,

A new, experimental procedure, called blastomere analysis before implantation, or BABI, has

been used to diagnose the CF status of an in vitro

fertilized embryo before implanting it in the woman’s

uterus. The technique involves extracting a single

cell from an embryo at about the eight-cell stage and

analyzing its CF mutation status. Recently, an

Photo credit: National Institute of Genera/ Medical Sciences

Left: Amniocentesis—the most widely used technique for prenatal diagnosis, generally at 16 to 18 weeks of a pregnancy. Cells shed by

the developing fetus are extracted from a sample of amniotic fluid that has been withdrawn from the expectant mother’s uterus by a

hypodermic needle. The cells are cultured and then can be analyzed for chromosomal defects, such as Down syndrome. DNA analysis

can also be performed (e. g., for CF mutation status).

Right: Chorionic villus sampling-a method of prenatal diagnosis that provides results as early as the 9th week of pregnancy. Fetal cells

from the chorionic villi (protrusions of a membrane called the chorion that surrounds the fetus during its early development) are suctioned

out through the uterine cervix and their DNA is analyzed. Preliminary results of this process can be obtained within a day.
148 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

unaffected baby that had been tested with BABI was

born to a couple in Lxmdon at risk for CF (70).

For some families, prenatal diagnosis for CF is

inconclusive. As in screening for carrier status,

couples receive test results that yield percentages

rather than certainties (54). There is speculation that

this ‘‘restructuring of uncertainty’ versus a‘ yes/no

answer’ will be confusing to individuals and cause

undue stress; pilot studies to examine levels of

anxiety in test populations before and after screening

are under way. Assessments of anxiety levels of

participants in other carrier screening programs are

limited in what they offer to CF carrier screening

because the levels of test uncertainty are not as great.

Women offered hemoglobinopathy carrier screening, for example, were found to manifest appropriate

levels of concern rather than undue anxiety, but the

test results were less ambiguous because the test is

more sensitive (59).

Informing Relatives and Inductive Screening

In any type of genetic screening, a real possibility

exists that test results will affect other family

members. In the usual genetic counseling setting, the

person being screened (the proband) is routinely

advised of risks to other family members. If, for

example, an individual is found to be a carrier for an

autosomal recessive disorder such as CF, the genetics professional informs the client that siblings also

each have a 50 percent chance of being carriers. In

most cases, the suggestion is made that the individual contact his or her siblings, and that they consult

with their personal physician or come to the same

clinic. The genetics professional does not usually

confirm that the proband has informed relevant

family members due to limits of confidentiality in

the counselor-client relationship. Some argue that

genetics providers should be legally permitted to

disclose such relevant information to relatives at

risk (76).

As discussed in chapter 5, breaching confidentiality to disclose medical information to relatives raises

legal and ethical issues. Not all families are emotionally and psychologically secure, Sibling relationships could impede full disclosure. Sharing highly

personal medical information that involves reproductive and health futures can cause personal

embarrassment or emotional stress for family members.

From the point of view of identifying the largest

number of carriers by screening the fewest number

of individuals, however, encouraging carriers to

notify relatives provides economic and pragmatic

benefits. Encouraging known carriers to refer siblings and first cousins for testing can detect a larger

percentage of at-risk couples. This approach, also

known as ‘‘inductive screening, ” improves the

efficiency of screening by 10 to 15 percent (15).

Testing those known to be at higher risk because of

family history is more effective than screening those

with unknown risk. In reality, complex psychological factors enter when family members of individuals with CF contemplate screening, and it cannot be

assumed that all will want to be tested (63).

OTA’s 1991 survey of genetic counselors and

nurse geneticists revealed that most families who

have a child with CF are not routinely seen in

genetics service settings, and few counselors have

routine contact with CF families (71). For inductive

screening to work, those providing health care and

counseling to CF families will have to actively

participate in referrals of relatives to genetics

centers. Less than 10 percent of respondents reported contacting previously identified CF families

regarding the availability of CF mutation analysis.

Post-Test Counseling

When attending a genetics clinic for reasons other

than prenatal genetic screening, people typically

come because they have or had an affected relative,

usually a child. These individuals tend to be aware

of the disorder, and the affected relative, rather than

a test, serves as the indicator of potential disease for

other offspring. As the number of genetic tests

administered to healthy individuals with no apparent

family history of genetic disease increases, genetics

providers might need to spend more time describing

the disorder to those with positive results.

Results are best reported in person, by the same

person who provided the pretest education—

although this is not always possible or practical (16).

If the test results are positive, prior contact might

have alerted the professional as to who else should

be informed, whose help might be needed on behalf

of the client (e.g., for emotional support), and

important information about the client’s lifestyle

and family (as well as financial and insurance

information).
Chapter 6-Education and Counseling ● 149

Followup counseling and support are also strongly

advised for persons with positive results. News of a

positive result can impede a person’s ability to

receive information on both emotional and practical

levels. Faced with positive results, most individuals

are unable to act until they overcome the shock and

possible denial that their fate or their children’s fate

could suddenly shift in a negative direction. People’s perceptions of their own health can worsen, for

example, as occurred for some when they were made

aware of their carrier status for Tay-Sachs disease

(42,43); such anxiety can be prolonged (83). Knowledge of carrier status can also have an impact on

reproductive intentions or behavior, including decisions relating to marriage or choice of marriage

partner (49,68).

Even in the best of all worlds, where consistent

counseling has been provided throughout the process, the effectiveness of counseling is sometimes

questionable. An analysis of nine studies on counseling published since 1970 concluded, “many

parents of children with a genetic disorder have an

inadequate understanding of the genetic implications of the disease, even after one or more genetic

counseling sessions’ (23). One survey found that

more than half of the 87 percent of people who came

to a genetic counseling center with inaccurate

knowledge of risk were still misinformed after

counseling (67). It is not clear whether they were

incrementally better informed,

The task of communicating genetic information is

formidable. Genetic counseling programs continually try to improve the process (74). A major

impediment to satisfactory genetic counseling has

been a profound lack of understanding of basic

genetics by almost everyone in the general public.

Anyone administering tests necessarily takes on the

role of educator as well as practitioner.

The Need for Better Public Education

Whether CF carrier screening programs are offered to prenatal or preconception populations,

public education efforts aimed at better understanding of genetic conditions and inheritance will be

increasingly essential. The need for better scientific

literacy has been a topic of great concern in recent

years. Even by the 12th grade, fewer than half of

students can use data in tables or graphs (72). A

recent survey of 1,006 Americans regarding attitudes about genetic testing revealed that fewer than

Photo credit: University of South Carolina School of Medicine

Genetic consultations can require longer office-visit time

because of the need for gathering detailed information

about the client and for followup counseling and support.

This genetic counselor is discussing the client’s

chromosome profile with her.

half were able to correctly answer 4 of 5 technical

questions regarding genetic testing (66).

Most counselors and nurses responding to the

OTA survey, however, indicated they spend little to

no time on general public education in schools and

communities (71). Thus, most people will rely on

their primary care provider for preliminary genetic

information. Survey respondents indicated that they

think primary care providers and public health

departments should play an active role in educating

the public about DNA tests for CF carrier status (71).

Public education programs for genetic diseases

have been nearly nonexistent since the programs

established under the National Genetic Diseases Act

(Public Law 94-278) were phased out in 1981. In

terms of public education, the National Science

Foundation has supported a teacher training program

in genetics for school teachers in Kansas, but there

is no similar program through NSF at the national

level (14). In the Kansas program, lead teachers were

trained to teach peer teachers in genetics. Teachers

who participated in the program showed a 3-fold

increase in genetics instruction at the high-school

level and a 22-fold increase at the elementary school

level (28). More recently, a project to prepare 50

selected science teachers per year for 3 years to

become State resource teachers in human genetics

received funds though the Department of Energy’s

Ethical, Legal, and Social Issues Program. Nevertheless, fewer than half the Nation’s elementary
2150 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

schools and about one-third of high schools make

science education a curriculum priority (72).

The importance of a period of community education before the implementation of genetics programs

has been demonstrated in sickle cell and Tay-Sachs

screening programs in the United States, and in

thalassemia screening programs in Sardinia and

Cyprus (app. B). More public awareness about

genetic diseases and tests could result in less time

needed for individual counseling. Experiences with

ß-thalassernia carrier screening in Sardinia and

Cyprus demonstrate the impact of public education.

Aggressive public education campaigns orchestrated in these countries placed information on the

disease and carrier screening on television and in

large department stores and factories, marriage

registry offices, general practitioners’ offices, and

family planning clinics. In Sardinia, the birth rate of

thalassemia-affected newborns fell from 1 in 250 to

1 in 1,200 (10). In Cyprus, genetics is taught in

school and screening is encouraged before marriage.

As a result, the time needed for counseling has

decreased as public education has increased (2).

In an ideal world, better education in the schools

would make individuals more aware of genetic risks

before they are confronted with genetic screening

programs. And if pregnant women are informed,

they might initiate genetics discussion with their

obstetricians rather than waiting to be informed (8).

STRATEGIES FOR SCREENING

VARIOUS POPULATIONS

Two key considerations in deciding how best to

implement routine CF carrier screening are the

clinical settings in which it will take place and the

target populations. Delineation of a target group (or

groups) determines other elements such as location,

educational approach and tools, time, format, types

of counseling, facilities, and publicity.

The NIH statement on CF carrier screening

emphasized the importance of preconceptional screening (53). Most pilot projects in the United Kingdom

are directed at preconceptional populations (ch. 10).

Pilot studies under way in the United States are both

prenatal and preconceptional (see following section). One program in Canada targets high school

students (35).

Newborn Screening

Numerous newborn screening programs exist for

genetic disorders such as sickle cell anemia and

phenylketonuria. These are programs intended to

screen for the presence of disease, although some

can also detect the carrier status of the newborn.

Wisconsin has performed statewide neonatal screening for CF disease since 1985, using the immunoreactive trypsin assay. Primary care physicians

have been cooperative in referring screened patients

to designated CF centers (47). But even newborn

screening for CF disease is not without controversy.

Evidence of heightened anxiety and disrupted maternal-infant bonding have been reported in cases of

false-positive diagnoses (7).

For at least two reasons, many believe that

newborn screening is an inappropriate and inefficient mechanism for carrier detection. First, newborns determined to be carriers must be tracked

through their reproductive years to ensure they are

aware of their carrier status. Second, detection of

newborn carriers might unnecessarily raise the

anxiety level of parents. Thus, newborn screening

for CF carrier status is not generally viewed as

acceptable (48). OTA’s survey of genetic counselors

and nurses bears this out; a minority of respondents

(33 percent) felt the newborn population would be an

appropriate target group for widespread CF carrier

screening (71).

Adolescent Preconceptional Screening

Some geneticists advocate screening at the highschool level (35). A recent nationwide survey of

American attitudes about, and knowledge of, genetic

tests showed better knowledge and more positive

attitudes in younger populations (66). Studies of

pregnant women known to be carriers of a hemoglobinopathy gene have shown that age is a predictor

of postcounseling knowledge-younger women

(and adolescents as young as 12 years old) are more

likely to understand genetic information (41). While

not routinely done in the United States, high-school

screening programs have been conducted in Canada

for some time (app. B). For any disease where

screening is done in childhood or adolescence,

however, the benefits of such screening, including

savings in inconvenience, resources, and anxiety,

must be balanced against the potential problems,

such as the possibility that an adolescent will be

falsely assigned to a low-risk group because of poor
Chapter 6---Education and Counseling ● 151

test sensitivity (thereby obviating further screening),

or the possibility of psychosocial harm to the child

as a result of identified carrier status (29).

Adolescents were not considered to be an appropriate target by the genetic counselors and nurses

surveyed by OTA (71). Less than 18 percent felt

individuals ages 13 to 18 years should be screened.

Only 6 percent felt that children ages 2 through 12

years should be screened.

Adults—Preconceptional or Prenatal?

Current debate surrounding CF carrier screening

focuses on whether the goals are best accomplished

by targeting preconceptional adults or pregnant

women. These approaches are not necessarily mutually exclusive. Many feel, however, that receipt of

troubling information during pregnancy is not desirable, and that it would be better for individuals to

know their risks before getting pregnant (39). Others

argue that individuals not facing a pregnancy are not

motivated to seek or use information on their carrier

status, but will wait until they are either planning a

family or starting a family before viewing such

information as useful (9).

CF carrier screening offered as part of primary

health care rather than prenatal care is likely to

encourage preconceptional CF carrier screening. For

most individuals, however, the first real opportunity

for carrier screening takes place post-conception

(22). It could well be that the primary responsibility

for providing CF carrier screening will reside with

the obstetrician, as has happened with MSAFP

screening. Sixty-six percent of respondents to OTA’s

survey identified pregnant women or couples as the

appropriate target population for CF carrier screening. Yet 88 percent generally identified adults in

their reproductive years as the appropriate target

group (71). While most respondents state that the

ideal population to target for carrier screening is the

preconceptional adult (71), in reality, the first target

population is likely to be the prenatal population

because it has been the traditional entry point into

genetic services for many people.

Pregnant women often have established a relationship with an obstetrician/gynecologist or prenatal clinic staff, who can provide information about

CF carrier screening. Ideally, individuals should

receive potentially emotionally loaded information

when they have the most latitude for reproductive

choice (figure 6- 1). Women in the early stages of

pregnancy have the choice to continue the pregnancy

or electively terminate it; attitudes regarding abortion of CF-affected fetuses indicate that prenatal

screening would only modestly reduce the incidence

of CF, as many couples with CF-affected children

speculate that they would not elect termination of an

affected fetus (1,77,78). Studies of pregnant women

screened for hemoglobinopathy carrier status have

shown little evidence that screening raised anxiety

(41). Pregnant women with fetuses at risk for

hemoglobinopathies are highly receptive to genetic

information (60) because they seek reassurance that

fetuses are not affected.

The increasing availability of genetic tests might

shift genetic services from specialized clinics, where

they are now usually located, to primary care

settings. This is likely to be especially true for tests

for disorders like CF. First, the possibility exists for

the clinical genetics community to become overwhelmed by the volume of tests and counseling. If

this occurs, genetic specialists will need to rely on

primary care providers and community and public

health institutions to bear some of the workload,

Two examples of public health models are Statesponsored MSAFP screening in California and

newborn screening programs for hemoglobinopathies and phenylketonuria. Second, some aspects of

medical genetics—specifically routine screening of

those with no family history of genetic disease—

could increasingly be considered less of a medical

specialty (tertiary care) and more a part of primary

care. Thus, genetics education must reach primary

caregivers, yet the average 4-year medical school

curriculum includes only 21.6 hours of genetics

instruction (57). Third, placing CF carrier screening

within the realm of obstetric care might decrease

out-of-pocket expenses to the client. As part of

routine care, insurers might be more likely to

reimburse CF carrier screening in the prenatal

population.

Overall, then, if carrier screening is to become

routine, it is likely that it will be offered as part of

family plarming or reproductive health, and the

medical specialty most likely to offer the test will be

obstetrics-a prospect some genetic specialists find

unsettling. Experience with MSAFP has shown that

despite the development of practice guidelines,

obstetricians often perform tests on pregnant women

without obtaining their consent (31). In addition,

obstetricians who do not screen for certain genetic

conditions in individuals at high risk could be at risk
152 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure 6-1---Decisionmaking in Premarital Carrier Screening

Artificial insemination or

implantation of embryo

/

I t 1 I t I

1 I I I

SOURCE: Office of Technology Assessment, based on F. Cohen, C/Mea/ Genetics in Nursing Practice (Philadelphia, PA: Lippincott, 1984).

for malpractice or wrongful birth suits (64). This

perceived tension—lack of informed consent coupled with pressure to screen—leads many in the

clinical genetics community to express concern

about premature widespread CF carrier screening

before adequate professional education is in place.

With regard to CF carrier screening, concern exists

that layers of uncertainty will inhibit informed

consent and that, ultimately, more harm than good

might be done.

The sickle cell and Tay-Sachs carrier screening

programs provide valuable information on the importance of prescreening education, understanding

the culture and values of the population being

screened, and optimizing the setting in which

screening occurs. Mistakes were made and lessons

learned (app. B). While CF carrier screening also

involves identification of carriers and high-risk

couples, it differs from these experiences because of

the sensitivity of the test and the larger number of

couples at risk. There is little experience in the

delivery of such complex information to large

populations (11). Initial experiences with MSAFP

screening revealed some confusion and concern on

the part of patients because of a high false positive

rate, limited test sensitivity, and apparent lack of

understanding within the obstetrics community about

the screening procedure (box 6-A).

PROFESSIONAL CAPACITY

As mentioned earlier, OTA reserves the term

genetic counselor to specifically describe master’ slevel individuals certified as genetic counselors by

the American Board of Medical Genetics (ABMG)
Chapter 6---Education and Counseling ● 153

Photo credit: Diane Baker

Genetic counseling prepares the individual for both

positive and negative test results.

(or board-eligible) because legal distinctions in

licensing and third-party reimbursement exist among

the different types of practitioners. OTA uses the

term genetic counseling generically to refer to the

information delivery process that is performed by

genetic specialists, including physicians, Ph.D. clinical geneticists, genetic counselors, nurses, and

social workers. overall, approximately 630 individuals from the range of types of training are certified

by the ABMG to perform genetic counseling. (The

exams are given every 3 years so many practitioners

are board-eligible but have not yet taken or passed

the exam.)

At issue in considering widespread carrier screening for CF is whether there are enough adequately

trained health professionals to handle the volume of

tests. One study estimated that a minimum of

651,000 counseling hours would be required annually if their maximum estimate of 6 to 8 million

preconceptional couples are screened for CF carrier

status (81). Considering the current number of

board-certified genetic counselors practicing in the

United States today, this translates to 17 weeks per

year from each genetic counselor to serve CF-related

clients (81). On the other hand, one estimate

suggests the supply of genetic specialists could

absorb routine carrier screening for CF, sickle cell

anemia, hemophilia, and Duchenne muscular dystrophy, assuming that obstetricians or other primary

care physicians perform the screening on pregnant

women, with referral of those with positive results to

genetics professionals (31).

The counselors and nurses surveyed by OTA

estimate that pretest counseling for CF carrier status,

regardless of family history, would take, on average,

1 hour (71). It is unclear to what extent increased

demand for CF carrier screening would strain the

current system. Current estimates undercount the

number of health care professionals who practice

genetic counseling and assume that counseling

would always be provided in a clinical genetics

setting by board-certified or board-eligible counselors. Such estimates also ignore the role that aggressive public education can play in improving pretest

knowledge (2,10). Improvements in public education could result in dramatically less time required in

formal counseling as could reliance on health

professionals not formally trained in genetics.

The following section addresses the traditional

roles played by master ’s-level genetic counselors

and presents nontraditional sources as possible

options for handling an increasing caseload.

Master’ s-Level Counselors

The master’ s-level genetic counselor is a relatively new addition to the health care system. In

1971, 10 graduates of the first such program entered

the workforce; in 1979, the National Society of

Genetic Counselors (NSGC) was incorporated as a

professional organization. Today, there are approximately 1,000 master’ s-level genetic counselors practicing in the United States.

Master’ s-level genetic counselors receive specialized multidisciplinary training and experience to

prepare them for counseling related to a wide variety

of genetic disorders and birth defects. They are

typically graduates from a 2-year master’s degree

program, during which time they receive didactic

course work in the principles and application of

human genetics, clinical and medical genetics,

genetic laboratory methods, and interviewing and

counseling. Genetic counselors are also trained in

social, ethical, legal, and cultural issues relating to

genetic diseases, principles of public health and

health care delivery systems, and education for the

lay and professional community (73). Over the past

20 years, master’ s-level graduate programs in genetic counseling have increased to 15; combined,
254 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

they produce approximately 75 graduates each year

(54).

Genetic counselors receive a minimum of 400

hours of supervised clinical training in at least three

clinical settings, including a general genetics clinic,

a prenatal diagnosis clinic, and a speciality disease

clinic. Until 1992, graduates were eligible to sit for

the certification examination in genetic counseling

by the ABMG, but the continuing certification of

these individuals by this body is unclear. In the past,

counselors were required to submit their credentials

and a logbook of 50 cases obtained in a clinically

accredited training site before taking the exam (54).

Genetic counselors typically work in university

medical centers or private hospitals in metropolitan

areas, and tend to be female, Caucasian, and married

(71). The mean gross salary in 1990 was $33,879

(56). The majority are board-certified or boardeligible by the ABMG and have been in clinical

practice for at least 6 years (71).

Training support for master’ s-level genetic counselors has been minimal. No financia1 support is

supplied by the U.S. Department of Health and

Human Services (DHHS) for the training of genetic

counselors or for improving genetics education in

medical schools (31). Through support to the Council of Regional Networks for Genetic Services

(CORN), the DHHS Bureau of Maternal and Child

Health and Resources Development provides support for some continuing professional education

programs for physicians and postdoctoral students,

but not for master’ s-level counselors.

As the profession has developed, master’ s-level

counselors have begun to consider taking the role of

trainer of other health professionals. This role with

respect to “single-gene counselors, ” discussed in

the following section, could serve as an example of

how an increase in CF-related counseling could be

handled.

Non- Master’ s-Level Counselors

In some clinical settings, a role has been created

for a non-master’ s-level individual to meet the

demand for patient education related to one diagnostic category of disease. In other settings, such

individuals assist genetic counselors in overcoming

cultural, linguistic, geographic, or economic barriers: The OTA survey of genetic counselors and

nurses in genetics, for example, revealed that only 14

percent were fluent in a language other than English

(71). Individuals who assist genetic counselors,

often called ‘‘single-gene counselors, ’ or “nonmaster’ s-level counselors, ’ do not have the same

training as master’ s-level genetic counselors and

have not been eligible for ABMG certification. With

the growth of genetic services and increasing

demands on the time and resources of traditionally

trained counselors, use of these individuals has

raised debate.

Advocates of single-gene counselors cite the

current shortage of genetic counselors-the NSGC

maintains a jobs hotline, and has consistently over

the last 3 years posted at least 35 unfilled positions

at a given time. Single-gene counselors could also

improve the quality of service in underserved,

culturally diverse populations that are disproportionately affected by a particular genetic disease

(54).

Those opposed to single-gene counselors express

concern about what they view as a lack of genetics

training. Some view them as a possible threat to the

professional status of genetic counselors. There is

also concern about whether single-gene counselors

have a broad enough view of clinical genetics to

identify complex and obscure risks of other genetic

disorders in their patients. Since taking a family

history often exposes previously unknown or undiagnosed genetic disorders or predispositions, individuals who focus on one category of disease might

not recognize the need to further investigate peripheral information.

An NSGC task force has recommended that the

society:

Ž

●

●

●

●

acknowledge the current and predicted personnel needs for genetic counselors as well as the

shortage of master’ s-level genetic counselors;

recognize the existing use of non-master’ slevel counselors and the benefits they offer;

educate the NSGC membership regarding the

potential use of these individuals;

support the use of non-master’ s-level counselors in specific settings where genetic counselors can be involved in training, evaluating, and

supervising these individuals; and

establish a committee to collaborate with other

organizations.

Genetic counselors have been involved in developing and conducting training programs as well as

supervising hemoglobin trait counselors in several
Chapter 6-Education and Counseling ● 155

States. Programs in California and Massachusetts,

for example, employ non-master’ s-level professionals to conduct genetic counseling for sickle cell

disease (26).

Other Health Professionals

Integration of other health professionals, such as

nurses, nurse practitioners, social workers, dietitians, psychologists, and physicians, into the existing genetics network will supplement the skills of

the traditional genetic counselor. Similarly, the

involvement of other health care professionals will

be important to increasing public awareness and

education. If CF carrier screening were to become

routine, clinical geneticists would have to become

more involved in the delivery of community (public

health) genetic services, the education and training

of other health care professionals, and public education.

Nurses in Genetics

There are nearly 2 million registered professional

nurses in the United States, many involved in

maternal and child health nursing. These professionals provide a unique potential to contribute to the

effective deliver-y of genetic services. Efforts are

under way to encourage the incorporation of clinical

genetics into the curricula of schools of nursing at

both the graduate and undergraduate level (32). The

need for better genetics education in nursing stems

from the recognition that genetics is generally within

the realm of tertiary care; thus, genetic specialists are

not always in the position to screen every individual

needing genetics referral (32). That is, individuals

who need genetic services must first be identified by

the primary health care professional, and in some

settings—such as community, occupational, or

school health—nurses are the only link with the

health care system (27). Thus, nurses can assist in

the identification, education and counseling, and

followup of patients (25,32). Yet while nurses can be

a valuable part of genetic services, to date they are

a largely untapped resource (27).

Opportunities for clinical genetics experience in

nursing programs vary. Genetics is generally a part

of the nursing school curriculum, but again, variability exists among programs (27). Four of the 200

universities in the United States that offer graduate

degrees in nursing have established programs providing a master’ s-level genetics major (27). A small

number of nurses, particularly those in maternal and

child health nursing, have focused on genetics in

order to sit for the genetic counseling examination

given by the ABMG (27,33). There are over 100

nurses who are employed in genetics, according to

the International Society of Nurses in Genetics.

Governmental support of genetics education for

nurses has been through the Health Resources and

Services Administration, Bureau of Health Care

Delivery and Assistance, Division of Maternal and

Child Health (26).

Social Workers and Public Health Professionals

Social workers can play an important role in

genetic services delivery, particularly in undeserved communities. Nevertheless, only 9 of almost 100

accredited social work graduate programs in the

United States offer special courses on genetic topics

(28).

Similarly, public education in genetics requires

increased commitment at the public health level.

This requires educating public health professionals

about pertinent issues related to medical genetics

and changing the attitudes and staffing patterns of

key State agencies (17,18). Yet a survey of curricula

at member schools of the Association of Schools of

Public Health indicated a decrease in the number of

schools offering human genetics as a major area of

study (28). Few schools of public health offer

genetics as part of their curriculum, and in none is it

required (62).

THE FEDERAL ROLE I N

DECIDING THESE ISSUE S

In 1990, NIH convened a consensus workshop on

‘‘Population Screening for the Cystic Fibrosis Gene. ’

Participants concluded that tests should be offered to

all individuals and couples with a family history of

CF. However, the group did not recommend population-based screening for individuals and couples

with a negative family history, because:

● With a sensitivity [at the time] of 70 to 75

percent, only half of the couples at risk can be

identified.

. The frequency of the disease and the different

mutations vary according to racial and ethnic

background, so that important laboratory and

counseling modifications would be required in

different populations,
156 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

●

●

The

There are substantial limitations on the ability

to educate people regarding the use of an

imperfect test.

Without more definitive tests, about 1 in 15

couple---those in which one partner has a

positive test and the other has a negative

test—would be left at increased risk (approximately 1 in 500) of bearing a child with CF

(53).

workshop concluded that these difficulties

would be substantially reduced if the test were

improved to 90 to 95 percent accuracy. Populationbased CF carrier screening was considered appropriate if a 95 percent level of carrier detection were

achieved. Additional screening guidelines were

developed, including:

Screening should be voluntary and confidentiality assured.

Informed consent must be obtained via pretest

education.

Providers of screening have an obligation to

provide adequate education and counseling.

Quality control of all aspects of laboratory

testing, including systematic proficiency testing, is required and should be implemented as

soon as possible.

There should be equal access to counseling.

The NIH group felt that legislative action regarding CF carrier screening was not required unless it

became evident that individuals identified as

carriers were suffering from discrimination, either

through employment or insurance. It described the

most appropriate group for population-based carrier

screening as individuals of reproductive age, preferably preconception. Furthermore, the NIH group

agreed that the optimal setting for carrier screening

is through primary health care providers or via

community-based screening. It concluded that newborn or childhood screening would be inappropriate.

The NIH statement stressed the importance of

providing nondirective genetic counseling for individuals determined to be carriers. Finally, the group

called on the Federal Government to fund pilot

projects to investigate research questions in the

delivery of population-based screening. The pilots

were envisioned to address the effectiveness of

educational materials, the level of use of screening,

laboratory aspects, counseling issues, costs, and

beneficial and deleterious effects of screening (53).

NIH Clinical Assessments

Responding to increasing calls for a Federal

initiative to evaluate population carrier screening

(58), the Ethical, Legal, and Social Issues Working

Group of the National Center for Human Genome

Research (NCHGR) hosted a workshop in September 1990 to discuss an appropriate role for NIH. This

workshop concurred with earlier statements that

clinical evaluations of alternative approaches to

genetic education, testing, and counseling were

needed to establish the professional practices that

should govern widespread CF carrier screening. In

stressing the importance of setting professional

standards as early as possible, CF mutation analysis

was viewed as a prototype for future DNA-based

genetic tests.

In January 1991, NCHGR, the National Institute

of Child Health and Human Development (NICHD)

and the National Institute of Diabetes and Digestive

and Kidney Diseases (NIDDK) invited a group of

consultants to advise NIH on the appropriate issues

to be addressed through pilot studies. They arrived

at six Questions:

●

●

●

●

●

☛

L

What are the levels of understanding of, and

interest in, CF carrier screening among different patient populations?

What are the optimum forms and levels of

pretest education for different patient populations?

What are the accuracy and cost effectiveness of

various types of tests?

What are the best approaches to post-test

counseling, in terms of patient understanding

and psychological health?

What are the optimum settings for providing

CF carrier screening services?

What record-keeping and reporting policies

best protect against breaches of confidentiality,

stigmatization, and discrimination?

The consultants recommended that NIH develop

a consortium of multiple studies, each addressing

some subset of the overall agenda. Such an approach

would allow for standardization across the participating groups in terms of evaluation measures and

tools, cost accounting, laboratory quality control,

and human subjects protection. It was also recommended that NIH provide support to underwrite the

current laboratory costs of the assay during these
Chapter 6---Education and Counseling ● 157

clinical studies, to improve access to the pilots by all

interested persons.

In April 1991, NCHGR, the National Center for

Nursing Research, NICHD, and NIDDK issued a

request for applications (RFA) for clinical evaluations related to CF carrier screening. The grant

competition was open to nonprofit and for-profit

organizations, including universities, public health

departments, and voluntary organizations. The award

period is for up to 3 years, and is renewable.

Originally, the RFA specifically excluded laboratory costs of the assays as eligible for grant support,

since they were considered part of the clinical care

of the individuals involved in the studies. Applicants

were urged to obtain additional institutional and

corporate support for these costs. (After the grants

were awarded, the exclusion of test cost was

rescinded for those studies involving subjects without a family history of CF.) Another requirement

was that minorities and women were to be sufficiently represented in study populations.

In September 1991, NIH awarded eight grants to

seven research teams around the country (box 6-B).

A consortium approach to the pilot projects has been

adopted: Grantees meet in workshops to coordinate

and share information. “The underlying goal of

these studies is to help determine whether CF

mutation analysis should remain focused on members of families already known to be at risk, or

whether it is feasible to offer the test more widely in

an ethically acceptable manner” (52).

For fiscal year 1993, NCHGR announced that it

intends to collaborate with the National Cancer

Institute to begin pilot projects to help health care

Box 6-B-Clinical Studies of Testing, Education, and

Counseling for Cystic Fibrosis Mutations, National Institutes of Health

In October 1991, three components of the National Institutes of Health-the National Center for Human

Genome Research, the National Institute of Child Health and Human Development and the National Center for

Nursing Research-launched a 3-year research initiative to optimize parameters for educating and counseling

individuals who want to& screened for CF mutations. The research teams supported under this initiative coordinate

their efforts. Where appropriate, some features of the research, such as evaluation measures and tools, cost

assessment, laboratory quality control procedures, and human subjects protections have been standardized across

sites. U.S. research teams at seven sites will conduct eight studies:

University of North Carolina, Chapel Hill, NC, “An Evaluation of Testing and Counseling for CF Carriers”

($2.31,916). C1Ose relatives of CF patients will receive pretest education either from a pamphlet in a private

physician’s office or in a traditional genetic counseling setting. The investigators will also assess the effectiveness

of a pre-genetic-counseling video for CF carrier screening clients. Both before and after receiving the results of CF

carrier tests, subjects will be assessed to determine genetic and medical knowledge, psychological status, and

selected health behaviors.

Children’s Hospita[ Oakland Research Institute, Oakland, CA, “Perception of Carrier Status by Cystic

Fibrosis Siblings” ($73,196). By interviewing the adult siblings of (CF patients and the (CF siblings’ spouses, the

investigators will identify factors motivating or interfering with the pursuit of CF carrier testing in siblings, and

assess their spouses’ level of interest in screening. In addition to examining interest in testing, this study aims to

assess the levels of understanding of test results and knowledge of medical aspects of CF, as well as to assess

psychological functioning of CF siblings and spouses following testing.

Vanderbilt University, Nashville, TN, “Cystic Fibrosis Screening: An Alternative Paradigm” ($206,513).

This study aims to determine the feasibility of a (CF carrier screening program that incorporates pre- and post-test

education for people with negative screening tests and provides personal counseling primarily for those who test

positive for CF carrier status. Written and video materials will be developed. The investigators will examine various

settings for provision of carrier screening, determine the factors that affect a couple’s decision whether or not to be

screened for CF carrier status, and determine general acceptance of population screening.

University of Rochester, Rochester, NY, “Testing and Counseling for Cystic Fibrosis Mutation” ($274 ,110).

CF carrier tests will be offered to women of reproductive age to determine what proportion desire it, what proportion

of women who are tested adequately comprehend the significance of the results, and what proportion of partners

(Continued on next page)
158 ● Cystic Fibrosis and DNA Tests: Implications of Currier Screening

Box 6-B---Clinical Studies of Testing, Education, and

Counseling for Cystic Fibrosis Mutations, National Institutes of Health-Continued

of the screened women decide to be screened themselves. Anxiety, lack of comprehension, requests for prenatal

diagnosis despite low risk, and the costs of the program will be assessed.

UCLA School of Medicine, Los Angeles, CA, “Cystic Fibrosis Mutations Screening and Counseling”

($179,067). Women of reproductive age and the partners of those who test positive will be screened. The target

population includes large numbers of Hispanic and Asian Americans, two groups that have not been studied

extensively for either their CF mutation frequencies or their response to screening and counseling. Pre- and post-test

questionnaires will be used to determine level of understanding of CF, predictors of consent to screening, and

emotional responses to implications of the test results in the various ethnic and socioeconomic subgroups. Strategies

of pre- and post-test counseling will be compared for their effectiveness.

Johns Hopkins University, Baltimore, MD, “Ethical and Policy Issues in Cystic Fibrosis Screening”

($314,449). This project focuses on families and individuals receiving care from a health maintenance organization.

It seeks to determine the level of interest in learning more about CF and factors that distinguish those who are

interested in participating in a CF education program from those who are not. The focus consists of three elements:

education of the study population, determination of the characteristics that distinguish those who agree to have the

CF carrier test from those who decide not to be screened, and comparison of the responses of individuals identified

as CF carriers and those identified as probable noncarriers, with emphasis on the extent to which these responses

are influenced by marital status, or carrier status of the partner. All participants who test positive for CF carrier status

and a sample of those who test negative will be followed for 1 year.

University of Pennsylvania, Philadephia, PA, “Prescriptive Decision Modeling for Cystic Fibrosis

Screening” ($197,634 and $180,201). Decision theory and economic techniques will be used to model

decisionmaking about CF carrier screening that addresses the following issues: who should be offered carrier

screening and the best method for screening couples; the best course and sequence of further screening and treatment

following initial results; rescreening individuals who have been screened in the past for CF mutations as more

mutations are uncovered; the anticipated impact of future technologic innovation on CF carrier screening and

treatment; tradeoffs between monetary and nonmonetary effects that the alternative answers to these questions

imply; and differences in responses of various groups (i.e., patients, health care providers, and insurance companies,

which have varying financial, psychological, and moral perspectives).

In addition, a team will conduct a clinical study, How Much Information About the Risk of Cystic Fibrosis Do

Coup/es Want?, to complement the theoretical work. This project will analyze the decisionmaking processes of

preconceptional and prenatal couples who are offered CF carrier screening one partner at a time, and, in the event

of a negative result for the first partner, whether or not the couple chooses to have the second partner screened. The

appropriate timing of CF carrier screening, as well as the amount that should be performed, will be investigated.

SOURCE: National Center for Human Genome Research, National Institutes of Health, October 1991.

professionals understand the best way to educate and create the Maternal and Child Health (MCH) Block

deliver genetic tests to patients who ask for them,

specifically genetic tests related to colon and breast

cancer (75).

Funding for Genetic Services

Recent Federal support for genetic services, and

thus salaries, has been minimal. Prior to 1981,

genetic programs could apply through their State for

funds under the National Genetic Diseases Act. The

Omnibus Reconciliation Act of 1981 (Public Law

97-35) replaced the National Genetic Diseases Act

and amended Title V of the Social Security Act to

Grant (ch. 2). This resulted in a drastic reduction of

direct Federal support for genetic services not

related to newborn screening (38). States that had

received Federal support in the past now had to rely

on the discretion of their State agencies and compete

with other public health initiatives for diminishing

dollars.

In fiscal year 1990, Federal and State funds for

genetic services other than newborn screening totaled about $34 million, of which the Federal share

was approximately $12 million (table 6-5). Other

sources of finds that States used for genetic services
Chapter 6---Education and Counseling ● 159

Table 6-5-Total Funding for Genetic Services by State, Fiscal Year 1990a

Maternal and

Child Health Other

State Total funds block grant Federal State Other

AL. . . . . . . . . . . . $ 228,000

103,000

524,600

984,200

16,673,300

403,000

371,400

145,800

481,200

1,070,300

1,567,000

318,900

246,900

292,000

843,100

935,000

50,000

291,000

388,600

293,400

798,300

716,100

725,000

256,400

333,300

1,617,000

423,400

202,000

582,100

152,300

500,700

635,400

26,654,200

2,152,900

99,900

3,558,500

386,400

599,000

779,800

107,500

1,355,000

300,000

112,600

2,332,900

4,311,900

197,000

235,000

755,000

1,300,000

375,000

540,300

125.000

$24,000

103,000

0

0

0

0

0

0

40,000

0

162,700

102,000

123,400

262,800

254,200

0

0

171,700

0

60,000

400,300

0

0

51,900

0

180,000

0

167,700

54,400

38,100

197,200

31,000

1,755,300

344,500

15,000

282,200

236,400

35,200

649,000

0

0

0

64,200

291,600

415,600

197,000

103,700

513,400

650,000

155,000

47,300

0

0

$218,600

0

470,200

0

0

0

220,700

0

0

216,900

0

0

o

0

0

0

0

0

632,500

0

135,800

173,300

0

59,400

0

80,000

0

160,700

0

849,800

0

0

0

150,000

0

130,800

0

155,000

0

0

0

201,800

0

0

0

0

0

0

125,000

$60,000

0

306,000

574,60@

2,163,800

27,000

371,400

145,800

220,500

1,070,300

1,404,300

0

0

0

149,300

860,200

50,000

0

388,600

233,400

398,000

83,600

100,000

68,700

0

1,437,000

0

34,300

217,500

91,400

142,800

604,400

1,260,000

1,808,400

0

1,552,400

0

121,500

0

25,000

1,200,000

0

48,400

1,808,000

2,300,000

0

99,400

241,600

0

0

0

0
160 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

include provider-in-kind services, third-party reimbursement, and user fees. These funding mechanisms provided an additional $45.6 million for at

least 26 States (44).

Support for education, training, and services of

rnaster’s-level genetic counselors and other genetics

personnel also comes chiefly through the MCH

block grant and has declined precipitously. MCH

genetics laboratory training grants totaled just under

$1 million in 1991 spread among 9 States through

Special Projects of Regional and National Signifi

cance (SPRANS) monies, down from $2.6 million in

1981. In real purchasing power, this decrease

represents a decline of about 76 percent. Total

SPRANS funding, not just that devoted to training,

but to provide seed money for services, education,

Figure 6-2-Federal Support of Genetic Services

Through the Special Projects of Regional and

Nationa Significance (SPRANS), 1978-91

. . . .

t I 1 1 1 I I I I 1 I I I

78 79 80 81 82 83 84 85 86 87 88 89 90 91

Fiscal year

------ Actual — Real purchasing power adjusted

to 1987 constant dollars using the

Gross Domestic Product implicit

price deflator

SOURCE: Office of Technology Assessment, based on E. Duffy, Maternal

and Child Health Bureau, U.S. Department of Health and

Human Services, Rockville, MD, personal communication,

February 1992.

and technical assistance demonstration projects has

also declined in real purchasing power since 1981

(figure 6-2). In addition to Federal funding, at least

25 States devote State monies to education, technical assistance, and training (table 6-6) (44).

RESULTS OF

NONFEDERAL PILOTS

In the absence of federally sponsored pilot projects to evaluate CF carrier screening, several public

and private institutions began to systematically

screen subsets of the population-pregnant women

and their partners, preconceptional teenagers and

adults, and fetuses. While most are collecting data

on the incidence of carrier status and mutation

frequencies, some are also following psychosocial

issues, such as levels of anxiety and retention of

information. The various populations targeted for

screening and the strategies used reflect the lack of

consensus on the best approach to CF carrier

screening. Some of these privately funded pilot

projects are described in the following section.

Because most were initiated at least one year before

Table 6-6-Funding for Genetics Education, Technical

Assistance, and Training, Fiscal Year 1990a

State Funding level Percent of totalb

$14,000

6,800

20,400

10,200

19,000

29,200

467,500

16,900

98,000

372,900

320,000

166,700

80,800

27,400

195,200

215,300

19,500

221,500

69,800

58,300

14,800

260,000

33,400

216,400

10,000

13.1

4.7

1.3

3.2

7.7

10.0

50.0

4.4

12.3

52.1

44.1

50.0

5.0

7.8

30.7

10.0

5.0

37.0

62.0

2.5

7.5

20.0

8.9

40.0

8.0

a Figures not available for States not listed.

b Calalatd as a percentage of genetic services funding (excluding

newborn screening) from State, Federal, and other sources.

SOURCE: F.J. Meaney, “CORN Report on Funding of State Genetic

Services Programs in the United States, 1990,” contract

document prepared for the U.S. Congress, Office of Technology

Assessment, April 1992.
Chapter 6---Education and Counseling ● 161

the NIH studies commenced, these efforts have more

data.

Baylor College of Medicine: Prenatal and

Preconceptional Carrier Screening of Couples

From 1990 through 1991, Baylor College of

Medicine (Houston, TX) processed more than 1,800

samples for CF carrier screening and testing, using

six mutations at 84.5 percent sensitivity. Baylor

employs a two-step approach. First, both partners are

concurrently screened for DF508+5. Anxiety of

pregnant women who test positive and must wait for

the results of their partner’s test is reduced if both

samples are processed simultaneously, rather than

sequentially. Second, partners of identified carriers

are subsequently analyzed for 12 additional mutations at no extra charge (24).

The original Baylor population was a mix of

prenatal and preconceptional couples, many related

to affected individuals. Of the high-risk group, 64

at-risk pregnancies were diagnosed. Of these 64, 14

affected fetuses were found; half of the pregnancies

were electively terminated. Sixteen carrier fetuses

were identified. Of those couples found to be +/-, no

pregnancies were terminated and there did not

appear to be undue anxiety. None of these +/-couples

requested prenatal fetal diagnosis, Six couples in

1991 were identified as +/+ prior to conception (24).

Starting in September 1991, screening has been

offered to all couples of reproductive age who have

contact for any reason with Baylor’s genetic services. Again, couples are screened, rather than

individuals, at a charge of $100 per couple. Identified carriers are encouraged to refer their relatives

for testing.

Cornell University Medical College:

Prenatal Carrier Screening

Since April 1990, Cornell University Medical

College has offered CF carrier screening to couples

with a negative family history for CF who are

enrolled in the prenatal diagnosis program (primarily for advanced maternal age). In 1992, screening

has been extended to all couples of reproductive age

coming to the genetic service, whether or not

pregnancy is involved.

Initially, one partner was screened for DF508

mutation only; the W1282X mutation was added

later because 30 percent of the Cornell couples are

Ashkenazic Jews. If the partner is positive, followup

testing of the other partner is done using six

mutations. More than 500 couples have been

screened to date using mouth rinse specimens. At a

charge of $100 per couple, about 33 percent choose

to participate. Those who choose to participate cite

an interest in learning about the health of the fetus.

Those who choose not to participate primarily cite a

perceived low carrier risk and the fact that the

patient’s referring physicians had not specifically

recommended the test.

All those who participate in the screening are

informed (and in followup questionnaires, acknowledge) that the assays will miss some at-risk couples.

Virtually all agree that the screening should continue

and not be slowed until a greater proportion of CF

carriers can be detected, or limited to those ethnic

groups in which the detection rates are the highest

(19).

Genetics & IVF Institute:

Elective Fetal Screening

The Genetics & IVF Institute (Fairfax, VA) is a

clinical and Laboratory facility that provides integrated outpatient services in the areas of human

genetics and infertility. In 1990, the Institute began

offering CF carrier screening of fetal samples to an

unselected Caucasian population undergoing amniocentesis or CVS primarily for advanced maternal

age.

As of August 1991,4,782 consecutive Caucasian

patients undergoing a prenatal procedure were

offered concurrent CF carrier screening of their fetal

sample, on a self-paying basis. Initially, screening

only detected DF508, but for some time has included

DF508 and six other mutations. Of 3,013 CVS

patients, 1,327 (44 percent) elected screening. Of

1,769 amniocentesis patients, 370 (20.9 percent)

chose CF carrier screening. Three carrier fetuses

were found in patients with a family history of CF,

and 48 carrier fetuses, including a set of twins, were

found in patients with a negative family history. Of

these 50 couples, 12 declined further testing. In one

couple requesting further testing, both partners were

found to be DF508 carriers. In the other couples who

had further testing, only one partner in each carried

a mutation; all carried the DF508 mutation except for

one who carried the G542X mutation. No couples

chose to terminate the pregnancy based on these

results.
162 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Patients are called by a counselor or physician

after delivery of the baby to determine the pregnancy

outcome and apparent health of the child, to

determine if a sweat test was performed, and to

discuss retrospective attitudes toward CF carrier

screening (63).

Roche Biomedical Laboratories:

Prenatal Couples Screening

Roche Diagnostic Genetics, a national, fullservice commercial genetics laboratory, launched a

nationwide collaborative research study of CF

carrier screening in July 1991. Using a reverse dot

blot/ploymerase chain reaction method (ch. 4),

Roche intends to screen 20,000 couples in the United

States. Originally intended to last 6 months, participation has been less than expected, so the study has

been expanded to 1 year. Assays are performed on

bucca1 cell samples obtained at home using a buccal

brush, collected in tubes, and mailed to Roche

Biomedical Laboratories (Research Triangle Park,

NC). Roche believes the ideal patients are those who

are 15 to 16 weeks pregnant and are undergoing

MSAFP screening. The sample can be collected as

early as the first prenatal visit, week 8 of the

pregnancy. This ‘captive” population, believe Roche

officials, is more likely to volunteer as research

participants (3). A solicitation letter was sent to 100

obstetricians around the country introducing the

program.

Roche employs the two-step approach, although

samples will be collected simultaneously for both

partners. The woman’s sample will be screened first

for DF508, G551D, G542X, and R553X. These

mutations collectively account for about 85 percent

of all CF mutations, according to Roche. If the

woman’s sample tests negative for these mutations,

analysis is not performed on her partner’s sample.

The couple is then informed that they are at

diminished risk. If the woman tests positive for one

of the four mutations, then her partner’s sample is

tested for the same four mutations. If his sample is

negative, the couple is told they are at reduced risk,

and the woman is informed that she is a carrier. If the

sample is positive, the couple is referred to a genetic

counselor and advised of opportunities for prenatal

diagnosis.

Roche officials believe this approach avoids

undue anxiety on the part of a pregnant woman

found to be positive. Roche reports that this approach will detect 72 percent of at-risk couples and

85 percent of carrier females. As of the fall of 1991,

the subscription rate was 50 percent. There are no

plans to offer the screen to preconception individuals (3).

Hypothetically, if Roche screens 20,000 Caucasian couples, and assuming a carrier frequency of 1

in 25, some 800 women will be identiled as carriers.

If the partners of all 800 women are tested, 32 men

will be found to be carriers. Thus, out of 20,000

couples, at a detection rate of 72 percent, 23 at-risk

pregnancies will be identified. Because Roche will

not screen the male samples unless the female

sample is positive, however, the opportunity to

identify 768 male carriers is lost.

McGill University:

High School Carrier Screening

In Montreal, Canada, carrier screening for genetic

diseases, such as Tay-Sachs, is a common practice in

some high schools. In May 1990, nine students and

four biology teachers at four schools in the Montreal

area conducted a pilot study of attitudes in persons

tested for the DF508 mutation. Forty percent of the

nearly 600 students invited to participate in the

project did so. Of these, two carriers were found. The

carriers and their families were interviewed and

found to hold positive views about their new

awareness. Additional family members have been

tested at their own request. Followup questionnaires

showed that participants who received negative test

results were found to be reasonably well informed

about the CF clinical phenotype, its inheritance, and

its distribution. Most understood that a negative test

did not rule out carrier status and were satisfied they

had taken the test (35).

Permanence Medical Group, Inc. —Vivigen—

Integrated Genetics: Carrier Screening

of Pregnant Women

In November 1991, the Kaiser Permanence Health

Care System of Northern California undertook

screening of 5,000 pregnant Caucasian and Hispanic

women—with a negative family history only-for

CF carrier status. The analysis and cost of running

the samples is equally divided between Vivigen, Inc.

(Santa Fe, NM) and Integrated Genetics (Frarningham, MA). The samples are screened for six

mutations, at a sensitivity of about 85 percent.
Chapter 6---Eucation and Counseling . 163

Women are screened first. If positive, their partner’s

specimen is obtained and tested for 12 mutations.

Kaiser has developed an informational videotape

that is being tested on control and experimental

groups to determine its adequacy for educational

use. In addition, several psychosocial survey instruments are being used to assess patients’ understanding of the progression and genetics of CF both before

and after screening.

The pilot program will end after 5,000 samples

have been analyzed. At that time, Kaiser Permanence

will make a decision as to how to proceed with

general screening for members of its health plan. As

of March 1992, 78 percent of women offered CF

mutation analysis elected it (82).

SUMMARY AND CONCLUSION S

The prospect of a highly sensitive, inexpensive

assay for CF carrier status is not far into the future.

As the sensitivity approximates 90 percentl for the

general population, demand for carrier screening is

likely to increase as the medical profession concomitantly recognizes its increasing duty to inform

patients about the availability of the information.

The ambiguous nature of the information, however,

requires that the consequences of screening be fully

understood.

Public education can go a long way toward

preparing individuals for the decision of whether and

when to be screened. However, public education

campaigns related to family planning issues, such as

CF carrier screening, are unlikely to be sponsored by

the Federal Government. Thus, the clinical genetics

community will have to work with allied health

professionals and educators in designing and delivering information regarding CF carrier screening and,

for that matter, other genetic tests to come.

In addition, the clinical genetics community will

need to train other health care providers to help bear

the educational burden as CF and other genetic tests

become widely used. This expansion must maintain

the nondirective philosophy of traditional genetic

counseling. The Federal Government, through more

support for training and genetic services, could

facilitate this effort.

Because the current genetics infrastructure is built

around the concept of entry into genetic services

during the prenatal period or following the birth of

an affected child, adults involved in a pregnancy will

likely be the frost population to undergo routine CF

carrier screening—this despite recognition that preconceptional screening is considered by most to be

the optimal situation. Although adolescent screening programs appear to be successful in Canada, they

are as yet unproven in the United States. At this time,

widespread newborn CF carrier screening is unlikely.

Privately funded pilot studies have contributed

groundbreaking and timely data about test sensitivity, target population, participant education, and

patient response. As well, the Federal Government,

through its clinical assessments of CF carrier screening, is playing an important role in ex amining the

factors important to widespread carrier screening.

The lessons of the past, from Tay-Sachs, sickle cell,

and MSAFP screening programs, are instructive for

the

1.

2.

3.

4.

5.

6.

7.

8.

future.

CHAPTER 6 REFERENCE S

A1-Jader, L. N., Goodchild, M. C., Ryley, H, C., et al.,

“Attitudes of Parents of Cystic Fibrosis Children

Towards Neonatal Screening and Antenatal Diagnosis,” Clinical Genetics 38:460-465, 1990.

Angastiniotis, M., Cyprus Thalassaemia Centre, Archbishop Makarios III Hospital, Nicosia. Cyprus,

“Development of Genetics Services From Disease

Oriented National Genetics Programs,’ presentation

at the 8th International Congress of Human Genetics,

Washington, DC, October 1991.

Barathur, R., Roche Biomedical Laboratories, Research Triangle Park, NC, personal communication,

September 1991.

Benkendorf, J.L., and Bodurtha, J. M., “Human

Genetics Education Videoshare: Round One, ’ Anzerican Journal of Human Genetics 44:61 1-615, 1989.

Biesecker, L., Bowles-Biesecker, B., Collins, F., et

al., “General Population Screening for Cystic Fibrosis Is Premature, ’ American Journal of Human

Genetics 50:439, 1992.

Botkin, J. R., ‘‘Prenatal Screening: Professional Standards and the Limits of Parental Choice, ’ Obstetrics

and Gynecology 75:875-880, 1990.

Bowling, F., Cleghom, G., Chester, A., et al.,

“Neonatal Screening for Cystic Fibrosis,” Archives

of Disease in Childhood 63:196-198, 1988.

Bowman, J,E. “Invited Editorial: Prenatal Screening

for Hemoglobinopathies,” American Journal of

Human Genetics 48:433438, 1991.

1 As noted previously, dF508+6- 12 detects 85 to 90 percent of CF carriers in the general population but 95 percent in Ashkenazic Jews.
164 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

9. Brock, D. J., “Cystic Fibrosis,” Antenatal and Neonatal Screening, N.J. Wald (cd.) (New York, NY:

Oxford University Press, 1984).

10. Cao, A., “A Disease Oriented National Health

Service,” American Journal of Human Genetics

49(supp.):31, 1991.

11. Caskey, C. T., Kaback, M. M., and Beaudet, A.L.,

“The American Society of Human Genetics Statement on Cystic Fibrosis,’ American JournaZ of

Human Genetics 46:393, 1990.

12. Chase, G. A., Faden, R. R., Holtzman, N.A., et al.,

“Assessment of Risk by Pregnant Women: Implications for Genetic Counseling and Education,’ Social

Biology 33:57-64, 1986.

13. Clarke, A., “Is Non-Directive Genetic Counseling

Possible?,” Lancet 338:998-1001, 1991.

14. Collins, D. L., University of Kansas Medical Center,

Kansas City, KS, personal communication, September 1991.

15. Cox, T. K., and Chakravarti, A., “Detection of Cystic

Fibrosis Gene Carriers: Comparison of Two Screening Strategies by Simulations, American Jourruzl of

Human Genetics 49(Supp.):327, 1991.

16. Crisis Counseling and HIV Antibody Testing, Report

from the First Interdisciplinary Conference on Human

Imrnunodeficiency Virus Antibody Testing and Counseling, sponsored by Sarah Lawrence College and

Memorial Sloan-Kettering Cancer Center, Nov. 17,

1987.

17. Cunningham, G, C., and Kizer, K. W., “Maternal

Serum Alpha-Fetoprotein Screening Activities of

State Health Agencies: A Survey,” American Journal of Human Genetics 47:899-903, 1990.

18. Davis, J, G., “Invited Editorial: State-Sponsored

Maternal Serum Alpha-Fetoprotein Activities: Current Issues in Genetics and Public Health, American

Journal of Human Genetics 47:896-898, 1990.

19. Davis, J. G., New York Hospital, Cornell University

Medical College, personal communication, March

1992.

20. Earley, K. J., Blanco, J. D., Prien, S., et al. “Patient

Attitudes Toward Testing for Maternal Serum AlphaFetoprotein Wlues When Results Are False-Positive

or True-Negative, ’ Southern Medical Journal 84:

439442, 1991.

21. Edwards, J. H., and Miciak, A., “The Slash Sheet: A

Simple Procedure for Risk Analysis in Cystic Fibrosis,’ American Journal oflluman Genetics 47: 1024-

1028, 1990.

22. Elias, S. E., Annas, G. J., and Simpson, J. L., “Carrier

Screening for Cystic Fibrosis: Implications for Obstetrics and Gynecologic Practice, ’ American Journal of Obstetrics and Gynecology 164:1077-1083,

1991.

23. Evers-Kiebooms, G., and van den Berghe, H.,

“Impact of Genetic Counseling: A Review of

Published Follow-Up Studies,” Clinical Genetics

15:465474, 198’7.

24. Fernbach, S. D., Baylor College of Medicine, Houston, TX, personal communication, December 1991.

25. Fibison, W. J., “The Nursing Role in the Delivery of

Genetic Services,” Issues in Health Care of Women

4:1-15, 1983.

26. Fine, B.A., Northwestern University Mtxiical School,

Chicago, IL, personal communication, September

1991.

27. Forsman, I., “Education of Nurses in Genetics,”

American Journal of Human Genetics 43;552-558,

1988.

28. Friedman, J. M., and Blitzer, M., “ASHG/NSGC

&tivities Related to Education: Workshop on Human

Genetics Education,” American Journal of Human

Genetics 49:1127-1128, 1991.

29. Harper, P. S., and Clarke, A,, “Viewpoint: Should We

Test Children For ‘Adult’ Genetic Diseases?,” L.uncet 335:1205-1206, 1990.

30. Hodgkinson, K. A., Kerzin-Storrar, L., Watters, E.A.,

et al., “Adult Polycystic Kidney Disease: Knowledge, Experience, and Attitudes to Prenatal Diagnosis,’ Journal of Medical Genetics 27:552-558, 1990.

31. Holtzman, N. A., Proceed With Caution: Predicting

Genetic Risks in the Recombinant DNA Era (Baltimore, MD: The Johns Hopkins University Press,

1989).

32. Jones, S, L., “Decision Making in Clinical Genetics:

Ethical Implications for Perinatal Practice, ’ Journal

of Perinatal and Neonatal Nursing 111-23, 1988.

33. Jones, S. L., Genetics & IVF Institute, Fairfax, VA,

personal communication, December 1991.

34. Kahneman, D., and Tversky, A., “ThePsychologyof

Preference, ’ Scientific American 246:160-171,

1982.

35. Kaplan, F., Clew, C., and Scriver, C.R., “Cystic

Fibrosis Carrier Screening by DNA Analysis: A Pilot

Study of Attitudes Among Participants,” American

Journal of Human Genetics 49:240-243, 1991,

36. Keenan, K. L., Basso, D., Goldkrand, J., et al., “Imw

hvel of Maternal Serum Alpha-Fetoprotein: Its

Associated Anxiety and the Effects of Genetic

Counseling,” American Journal of Obstetrics and

Gynecology 164:54-56, 1991.

37, Kessler, S. (cd.), Genetic Counseling: Psychological

Dimensions (New York, NY: Academic Press, Inc.,

1979).

38. Lin-Fu, J. S., Genetic Services Branch, Maternal and

Child Health Bureau, U.S. Department of Health and

Human Services, Rockville, MD, persomal communication, April 1992.

39. Lipkin, M., Fisher, L., Rowley, P. T., et al., “Genetic

Counseling of Asymptomatic Carriers in a Primary

Care Setting, “ Annals of Internal Medicine 105: 115-

123, 1986.
Chapter Education and Counseling ● 165

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

Lippman-Hand, A., and Fraser,F.C.,‘‘Genetic Counseling-The Postcounseling Period: Parents’ Perceptions of Uncertainty, ” American Journal of Medical

Genetics 4:51-71, 1979.

Loader, S., Sutera, C. J., Walden, M., et al., “Prenatal

Screening for Hemoglobinopathies. II, Evaluation of

Counseling, ’ American Journal of Human Genetics

48:447451, 1991.

Marteau, T.M.., “The Impact of Prenatal Screening

and Diagnostic Testing Upon the Cognition, Emotions, and Behaviour of Pregnant Women, ’ Journal

of Psychosomatic Research 33:7-16, 1989.

Marteau, TM., ‘‘Reducing the Psychological Costs,’

British Medical Journal 301:26-28, 1990.

Meaney, F. J., “CORN Report on Funding of State

Genetic Services Programs in the United States,

1990,” contract document prepared for the U.S.

Congress, Office of Technology Assessment, April

1992.

McNeil, B. J,, Pauker, S, G., Sex, H. C., et al., ‘ ‘On the

Elicitation of Preferences for Alternative Therapies,

New England Journal of Medicine 306:1259-1262,

1982.

Miller, S. R., and Schwartz, R. H., “Attitudes Toward

Genetic Testing of Amish, Mennonite, and Hutterite

Families With Cystic Fibrosis, American Journal of

Public Health 82:236-242, 1992.

Mischler, E., et al., “Progress Report: Neonatal

Screening for Cystic Fibrosis in Wisconsin, ” Wisconsin Medical Journal 88: 14-18, 1989.

Modell, B., ‘‘Cystic Fibrosis Screening and Community Genetics,‘‘ Journal of Medical Genetics 27:475-

479, 1990.

Modell, B., Ward, R. H., and Fairweather, D. V.,

“Effect of Introducing Antenatal Diagnosis on Reproductive Behavior of Families at Risk for Tha.lassemia Major, ’ British Medical Journal 280;1347-

1350, 1980.

Nance, W. E., ‘‘Statement of the American Society of

Human Genetics on Cystic Fibrosis Carrier Screening,’ in press, 1992.

Nance, W. E., Rose, S. P., Conneally, P. M., et al,,

“Opportunities for Genetic Counseling Through

Institutional Ascertainment of Affected Probands,”

Genetic Counseling, F. de la Cruz and H.A. Lubs

(eds.) (New York, NY: Raven Press, 1977).

National Center for Human Genome Research, press

release, ‘‘NIH Collaboration Launches Research on

Education and Counseling Related to Genetic Tests,’

Oct. 8, 1991, Bethesda, MD.

National Institutes of Health, Workshop on Population Screening for the Cystic Fibrosis Gene, ‘‘Statement From the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis

Gene, ” New I England .lournal of Medicine 323:70-

71, 1990.

54.

55.

56.

57.

58.

59.

60.

61,

62.

63.

64.

65.

66.

67.

68.

69.

70.

National Society of Genetic Counselors, Wal.lirigford,

PA, personal communication, June, 1991.

National Society of Genetic Counselors Cystic Fibrosis Ad Hoc Committee, Genetic Testing for Cystic

Fibrosis:A Handbook for Professionals (Wallingford,

PA: National Society of Genetic Counselors, 1990).

Perspectives in Genetic Counseling 12:6, spring

1990.

Riccardi, V. M., and Schmickel, R. D., “Human

Genetics as a Component of Medical School Curricula: A Report to the American Society of Human

Genetics, ’ American Journal of Human Genetics

42:639-643, 1988.

Roberts, L., “Cystic Fibrosis Pilot Projects Go

Begging, “ Science 250:1076-1077, 1990.

Rowley, P.T., Loader, S., Sutera, C. J., “Do Pregnant

Women Benefit From Hemoglobinopathy Carrier

Detection?,’ Annals of the New York Acadkmy of

Sciences 565:152-160, 1989.

Rowley, P. T., Imader, S., Sutera, C. J., et al., “Prenatal Screening for Hemoglobinopathies. I. A Prospective Regional Trial,” American Journal of Human

Genetics 48:439446, 1991.

Schild, S,, “Psychological Issues in Genetic Counseling of Phenylketonuria, ’ Genetic Counseling;

Psychological Dimensions, S. Kessler (cd.) (New

York, NY: Academic Press, 1979).

Schull, W. J., and Hanis, C. L., “Genetics and Public

Health in the 1990s,” Annual Review of Public

Health 11:105-125, 1990.

Schulman, J. D., Genetics & IVF Institute, Fairfax,

VA, personal communication, March 1992.

Shaw, M. W., ‘‘Conditional Prospective Rights of the

Fetus,” Journal of Legal Medicine 5:63-1 15, 1984.

Shiloh, S., and Sagi, M,, “Effect of Framing on the

Perception of Genetic Recurrence Risks,’ American

Journal of Medical Genetics 33:130-135, 1989.

Singer, E., “Public Attitudes Toward Genetic Testing, ’ ‘ in Population Research and Policy Review

10:235-255, 1991.

Sorenson, J. R., kvy, H. L., Mangione, T. W., et al.,

“Parental Response to Repeat Testing of Infants

With ‘False-Positive’ Results in a Newborn Screening Program, ’ Pediatrics 73:183-187, 1984.

Sujansky, E,, Kreutzer, S. B., Johnson, A. M., et al.,

“Attitudes of At Risk and Affected Individuals

Regarding Presymptomatic Testing for Autosomal

Dominant Polycystic Kidney Disease, ” American

Journal of Medical Genetics 35:510-515, 1990.

Tabor, A., Norgaard-Pedersen, B., and Jacobsen,

J. C., “Imw Maternal Serum AFP and Down Syndrome, ” Lancet 2(8395):161-162, 1984.

Thompson, L., “Cell Test Before Implant Helps

Ensure Healthy ‘Test-Tube’ Baby, ” Washington

Post, Apr. 27, 1992.
166 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

71.

72.

73.

74.

75.

76.

77.

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and Genetic Screening: Policies,

Practices and Attitudes of Genetic Counselors—

ResuZts of a Survey, OTA-BP-BA-97 (Washington,

DC: U.S. Government Printing Office, forthcoming

1992).

U.S. Department of Education, 1990 Science Report

Card, National Assessment of Educational Progress

(Washington, DC: U.S. Government Printing Office,

1992).

Walker, A. P., Scott, J. A., Biesecker, B. B., et al.,

‘‘Report of the 1989 Asilomar Meeting on Education

in Genetic Counseling, American Journal of Human

Genetics 46:1223-1230, 1990.

Waples, C. M., Buswell, B. E., Martz, J. C., et al.,

“Resources for Genetic Disorders,’ Genetics Applications: A Health Perspective (Lawrence, KS: hamer

Managed Designs, 1988).

Watson, J. D., testimony before the House Appropriations Committee, Subcommittee on Labor—Health

and Human Services-Education, Mar. 25, 1992.

Wertz, D. C., and Fletcher, J. C., “Attitudes of Genetic Counselors: A Multinational Sumey, ’ American Journal of Human Genetics 42:592-600, 1988.

Wertz, D. C,, Janes, S. R., Rosenfeld, J. M,, et al.,

“Attitudes Toward the Prenatal Diagnosis of Cystic

Fibrosis: Factors in Decision Making Among Af78.

79.

80.

81.

82.

83,

fected Families,” American Journal of Human

Genetics 50:1077-1085, 1992.

Wertz, D. C., Rosenfeld, J. M., Janes, S.R., et al.,

“Attitudes Toward Abortion Among Parents of

Children With Cystic Fibrosis,” American JournaZ

of Public Health 81:992-996, 1991.

Wertz, D. C., Sorenson, J. R., and Heeren, T. C.,

‘‘Clients Interpretation of Risks Provided in Genetic

Counseling, American Journal of Human Genetics

39:253-264, 1986.

Wertz, D. C., Sorenson, J. R., and Heeren, TC.,

“Communication in Health Professional-Lay Encounters: How Often Does Each Party Know What

the Other Wants to Discuss?,” Information and

Behavior, vol. 2, B.D. Ruben (cd.) (New Brunswiclq

NJ: Transaction Books, 1988).

Wilfond, B. S., and Fost, N., “The Cystic Fibrosis

Gene: Medical and Social Implications for Heterozy -

gote Detection, ” Journal of the American Medical

Association 263:2777-2783, 1990.

Witt, D., Kaiser Permanence Medical Group, San

Jose, CA, personal communication, March 1992.

Zeesman, S., Clew, C. L., Cartier, L., et al., “A

Private View of Heterozygosity: Eight Year Followup Study on Carriers of the Tay-Sachs Gene Detected

by High School Screening in Montreal,” American

Journal of Medical Genetics 18:769-778, 1984.
Chapter 7

Financing
Contents

Page

OVERVIEW OF U.S. HEALTH CARE FINANCING . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Public Financing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Private Financing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

REGULATION AND UNDERWRITING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Regulation of Insuring Entities ... ..** .*. ... *.. **, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Regulation of Insurance Contracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Underwriting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

OTA SURVEY OF HEAETH INSURERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Demographics of the Survey Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

General Attitudes Towards Genetic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

REIMBURSEMENT FOR GENETIC SERVICES-OTA SURVEY RESULTS . . . . . .

Experiences of Genetic Counselors and Nurses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Health Insurers’ Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medicaid Reimbursement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER 7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Boxes

7-A. Self-Funded Employee Health Benefit Plans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

7-B. Open Enrollment and Blue Cross and Blue Shield Associations . . . . . . . . . . . . . . . . . 172

7-C. Life Insurance and Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

Tables

7-1. Health Care Coverage in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7-2. Number of People Insured by OTA Survey Respondents . . . . . . . . . . . . . . . . . . . . . . .

7-3. General Attitudes of Insurers Toward Genetic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7-4. Impact of Genetic Tests on Insurers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7-5. Economic Analyses of Genetic Tests and Genetic Counseling by Insurers . . . . . . . .

7-6. Reimbursement for Cystic Fibrosis Carrier Tests and Genetic Counseling . . . . . . . .

7-7. Medicaid Reimbursement for Genetic Procedures By State . . . . . . . . . . . . . . . . . . . . . .

7-8. Average Medicaid Reimbursement for Genetic Procedures . . . . . . . . . . . . . . . . . . . . . .

169

177

178

178

179

181

18

184
Chapter 7

Financing

Health care financing in the United States is not

monolithic: There are several forms of private

financing, as well as public financing. This chapter

provides a general review of health care financing in

the United States. It briefly discusses how each

entity deter-mines eligibility for coverage and describes how each is regulated. OTA has examined

the U.S. health insurance industry in greater detail

elsewhere (27).

This chapter also describes a 1991 OTA survey of

U.S. commercial health insurers, Blue Cross and

Blue Shield (BC/BS) plans, and the largest health

maintenance organizations (HMOs). This chapter

focuses on survey results of private sector insurers’

general attitudes towards genetic tests and their

reimbursement practices for genetic tests and genetic services. Chapter 8 reports on results from this

survey that pertain to the potential impact of genetic

information or genetic tests on access to health care

coverage.

OVERVIEW OF U.S. HEALT H

CARE FINANCIN G

Health care financing in the United States totaled

more than $800 billion in 1991 (15), Public finding

includes Medicare and Medicaid programs, as well

as the Civilian Health and Medical Program of the

Uniformed Services (CHAMPUS), which insures

military personnel and their dependents. Private

funding mechanisms include self-funded plans

(which generally are plans administered by large

employers), commercial health insurance plans,

BC/BS plans, and HMOs. Finally, membership in a

State high-risk pool—in the 25 States that have

them-is an option that is increasingly available to

individuals who cannot obtain private health insurance (table 7-1).

Public Financing

Most public spending for health services covers

six populations: low income individuals and others

eligible for Medicaid, those over age 65, military

personnel and their dependents, veterans, Federal

civilian employees, and Native Americans. As with

most workers in the United States, Federal civilian

employees receive benefits through their employer,

the Federal Government, through plans similar to

private sector plans. Native Americans are covered

under the Indian Health Service.

Medicaid

Medicaid is a joint State and federally funded

program for low income citizens and people with

disabilities. Administered by the States, it provides

medical assistance to an estimated 6 percent of the

U.S. population (25). Operating within Federal

guidelines, each State designs and administers its

own Medicaid program. Thus, Medicaid eligibility

requirements, services offered, and methods and

levels of payment to providers vary widely among

States, although a minimum Federal standard of

services must be covered. The adequacy of Medicaid

in ensuring access to health care in general, and

genetic services specifically, depends on these

State-specific features.

Medicare

For people over the age of 65 and some disability

recipients under age 65, Medicare is the primary

source of health insurance, covering about 12.6

percent of the U.S. population (32). People below

age 65 who are totally and permanently disabled can

become eligible for Medicare coverage after a

minimum waiting period. In this way, some adults

with cystic fibrosis (CF) (who have worked and

contributed to the Social Security system for a

period) can receive medical coverage through Medicare under the program’s disability provisions.

Table 7-1—Healt h Care Coverage in t he United States

apersons With private coverage could be covered under commercial

insurance plans, BC/BS plans, HMOS, or self-funded plans that offer these

options. Of those covered by commercial plans, people can be covered

under group plans, medically underwritten group pians, or individual plans.

bsome persons with public coverage also have private coverage.

SOURCE: Office of Technology Assessment, 1992, based on Health

Insurance Association of America, Source Book of Health

/nsurance 7991 (Washington, DC: Health Insurance Association of America, 1991); and U.S. Department of Commerce,

Bureau of the Census, Current Population Reports Series P-70,

No. 17, 1990.

–169–
170 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

CHAMPUS

Medical treatment is available for all active and

retired military personnel and their dependents at

Department of Defense (DOD) medical sites

through the Military Health Services System (MHSS).

CHAMPUS, a component of MHSS, provides health

care for certain dependents of active duty personnel,

military retirees, and their dependents. In 1989,

expenditures for medical care comprised $2.8 billion

of the $13 billion DOD budget (14).

State Pools

In response to citizens’ difficulties in obtaining

health care coverage, several States have established

health insurance pools for underinsured and uninsurable persons. As of December 1990, State legislation

creating State high-risk pools for such individuals

had been created in 25 States, but not all are

operating (14). Several additional States are considering legislation.

State insurance pools provide an opportunity for

many to purchase health insurance regardless of

circumstance or physical condition, although generally at a rate considerably higher than most other

individual plans. Although eligibility for the plans

varies from State to State, the basic criterion for

participation is denial of coverage by’other insurers.

To qualify for a State high-risk pool, an individual

typically must have been rejected for health care

coverage at least three times for reasons related to

medical risk factors (17,20).

State pools vary greatly in the type and amount of

coverage they provide. Premiums are paid by

enrollees, but are capped at a certain level. Enrollee

premiums help fund pools, with the balance of costs

financed by State revenues and insurers. Insurance

companies contribute funds to pools proportional to

their market share in the State. Self-funded plans

(described in a following section) are the largest

payers of health care in the United States, but are not

assessed premiums for State high-risk pools.

Because State pools insure individuals with the

highest risks for medical needs and do not have

broad-based financing, they have not been without

problems. The high-risk insurance pool in Florida,

for example, covers 7,600 people, but was closed for

new enrollments in April 1991 because of budget

problems (12). State high-risk pools often have large

deductibles, high premiums, and maximum lifetime

benefits.

Private Financing

For the majority of Americans, access to health

care-and the health insurance that makes such

access possible—is provided through the private

sector. Privately financed health insurance for medical expenses covers more than 189 million persons

through self-funded companies, commercial insurance companies, BC/BS plans, and managed care

programs (e.g., HMOS and preferred provider organizations (PPOS)) (14). Although the term health

insurance broadly includes various types of insurance-e.g., disability income or accident—this chapter focuses on health insurance for medical expenses

(also known as major medical expense policies).

Private health insurance exists in a variety of

forms. The majority of Americans obtain health

insurance coverage through employment-either

directly as employees or as family members of the

employed. The employer, in turn, contracts with a

commercial insurer, a BC/BS plan, or an HMO. Such

groups are both large, with no diagnostic tests or

physical examinations required for entry (i.e., no

medical underwriting) or small (i.e., require some

diagnostic tests or physical examinations, on which

the insurance contract’s coverage and costs are

based). An employer can also be self-funded,

meaning it does not pay premiums to an outside

insurer but instead pays its employees’ medical

claims out of its own resources—although selffunded companies can buy claims processing services from outside insurers (box 7-A). Finally,

persons without group coverage can seek individual

health insurance from commercial insurers, BC/BS

plans, or HMOs.

BC/BS plans provide both individual and group

coverage to more than 80 million Americans (16).

Nationwide, 73 BC/BS plans operate on a regional

basis—many enjoying significant shares of their

local health care coverage market-and all offer

some form of individual health coverage. Market

share and regional focus can play a pivotal role in

how a BC/BS plan underwrites its policies. That is,

unlike commercial insurers, BC/BS plans are regional and do not sell coverage outside a particuar

State, metropolitan area, or region. The market share

of many BC/BS plans-though decreasing in recent

years-has historically overshadowed that of any

individual commercial carrier, so that in some States

as much as half the population are BC/BS subscribers. A secure market position can shape underwrit-
Chapter 7-Financing ● 171

Box 7-A—Self-Funded Employee Health Benefit Plans

Since enactment of the Employee Retirement Income Security Act of 1974 (ERISA) (29 U..S.C. 1131 et seq.),

many companies have found it beneficial to self-fund their employee health insurance benefits. Under ERISA, a

company is viewed as an employer providing benefits, not an insuring entity, and so escapes State insurance

regulation. Self-funded plans, for example, need not comply with State laws that mandate health insurance contracts

to include specified benefits (e.g., minimum maternity coverage or alcohol and drug addiction treatment), nor

comply with certain antidiscrirnination standards applicable to insured plans. Self-funded plans are also exempt

from State insurance premium taxes and need not participate in insurance pools for high-risk individuals.

Self-funding is particularly attractive to multi-State employers that do not want to tailor their benefit plans to each

set of State laws. Today, the majority of the large group market is self-funded, leaving most of the group benefits

marketplace virtually unregulated by the States (33).

Self-funding means benefits are provided by an employer, which directly assumes most or all of the financial

risk for its employees’ health care expenses. Self-funded employers can use and retain earnings on a pretax basis

on money they must otherwise set aside in claims reserves, The actual value of these reserves varies from company

to company, but can represent a sizable portion of the annual premium. Many employers prefer to have the use of

their capital instead of holding it in reserve.

Although some self-funded companies administer their own plans, most use independent third-party

administrators-often other commercial insurers, BC/BS plans, or independent claims processors. In addition to

administrative services, some commercial insurers and BC/BS plans also provide stop-loss insurance, which allows

employers to self-insure their plan up to a certain dollar amount. Should a company have employee health care

claims exceeding this amount, the stop-loss plan becomes effective and the policy pays additional claims-i.e.,

stop-loss insurance protects an employer from a catastrophic claim (7).

SOURCE: Office of Technology Assessment, 1992.

ing policies allowing a plan, for example, to enroll insurance plans (14), although the net number of

high-risk applicants because the plan can spread

risks over a broader base.

BC/BS plans often operate under considerably

different regulatory conditions from commercial

carriers. Currently, BC/BS plans in 12 States have an

open enrollment period, during which all individuals

who apply for coverage are accepted regardless of

their health status (16) (box 7-B), although most

contracts have waiting periods for preexisting conditions. Some open enrollment plans are continuous

(accept all applicants throughout the year), whereas

others limit open enrollment to a designated number

of weeks.

One of the fastest growing areas of health

insurance in the last decade has been managed care

groups such as PPOS

1 and HMOs. HMOs are health

care organizations that provide comprehensive services to enrolled members for a fixed, prepaid amount

that is independent of the number of services

actually used. The market share for these plans has

increased at the expense of conventional health

HMOs declined by 22 in 1990, reflecting industry

consolidation. As of December 1990, there were 569

HMOs in the United States, with enrollment exceeding 36.5 million members (1 1).

As with other health insurers, HMOs are paid a

freed premium for each member. Unlike other

insurers, however, an HMO is financially responsible for its members’ medical costs only if the HMO’s

affliated providers are used (except for emergencies) (24). By assuming not only the insurance risk

but also the responsibility for providing their members’ health care, HMOs operate under significantly

different conditions from either BC/BS plans or

commercial carriers. Another important distinction

is that while commercial insurers and BC/BS plans

are governed solely by State regulations, many

HMOs voluntarily also adhere to Federal qualification standards. In order to become federally qualified, HMOs must meet certain financial, underwriting, and rate-setting standards and provide specified

medically necessary health services (10). More than

1 PPOS are similar to HMOS, but provide more flexibility in physician selection. They involve contractual arrangements with specitlc physicians

or provider organizations.
172 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 7-B-Open Enrollment and Blue Cross and Blue Shield Associations

When BC/BS plans were first offered in the 1930s, all applicants were accepted for coverage regardless of their

health status-i. e., open enrollment. Today, plans in 12 States have an open enrollment period, although most

contracts have waiting periods for preexisting conditions. The implications of such plans for the underwriting

process are significant. Because no individual standards of insurability are applied to open enrollment applicants,

adverse selection exists. Adverse selection occurs when applicants seek coverage because they are aware of medical

problems (and hence medical expenses) that are not yet evident to the underwriter.

Most plans attempt to hold down premium rates for open enrollment subscribers by providing less

comprehensive benefits than are offered in other plans. Other BC/BS plans require open enrollment subscribers to

pay higher premiums than underwritten applicants for identical coverage. Finally, open enrollment coverage of

high-risk applicants usually entails awaiting period before initial benefits are paid, and they often impose limitations

on coverage of preexisting conditions.

Some applicants to BC/BS open enrollment plans must furnish evidence of their health status, even though the

plans never deny an application. Individuals seeking health care coverage through an open enrollment program often

have the option of undergoing medical underwriting, and even a physical exam, to determine whether they qualify

for a more comprehensive benefit package at a lower rate. Additionally, health information may be required by the

underwriter to develop benefit limits, exclusion riders, waiting periods for preexisting conditions, or premium rates.

SOURCE: Office of Technology Assesement, 1992.

half the Nation’s HMOs are federally qualified, and Individual Health Insurance

74 percent of HMO enrollment is in federally

qualified plans (1 1). Federal qualification can be

important to consumers: If an HMO accepts nonMedicare individual members, they must be either

accepted at a community rate or rejected altogether.

Exclusion riders and rated premiums are prohibited.

Waiting periods as well as preexisting condition

waivers are not allowed. However, medical screening of individual applicants is permitted.

Despite the fact that most people in the United

States obtain health care through group plans, many

have no access to an employer-sponsored plan

because they are unemployed, self-employed, or

employed by companies that do not provide health

benefits. Thirty-six percent of companies with fewer

than 25 employees offered their workers health

insurance in 1990, compared to 87 to 99 percent of

larger employers (13). An individual who is unable

to obtain health care coverage through his or her

employer must generally seek individual health

insurance.

Persons who obtain health care through individual

health insurance policies-from 10 to 15 percent of

all persons with health insurance-usually have

their health status evaluated by the insurer to

determine whether they are insurable, and if so, at

what price (a process called rating). This evaluation

of the applicant’s risk is commonly referred to as

medical underwriting, and relies at a minimum on a

medical history questionnaire, and less frequently,

on other sources of information such as an attending

physician’s statement or medical tests. Applicants in

groups of 10 or fewer employees are often individually medically underwritten as well (8,21). Medium

to large groups with 10 to 25 or more members are

seldom, if ever, medically underwritten. Risk classification is also generally not used in employer-sponsored/
Chapter 7---Financing ● 173

! I

I

I

I

1

Photo credit: Office of Technology Assessment

A Blue Cross and Blue Shield Association application for individual health insurance.
174 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

group plans. Large group plans accept all eligible

employees regardless of characteristics such as age,

sex, or health. However, most individual, medically

underwritten groups and large group plans have

restrictions on preexisting conditions.

Individual insurance operates on the principle that

the cost of insurance should be proportional to the

risks involved. Most applicants for individual insurance receive standard rates (22). Individuals applying for insurance whose potential losses might be

large, however, can expect to pay higher premiums—

often called rated premiums-than those whose

potential losses are expected to be less. Individuals

might also be accepted at standard rates, but with

certain waivers excluding health care coverage

related to specific conditions. Some applicants

might be accepted with both an exclusion waiver and

at a rated premium. Applicants with significant

disease can be denied insurance altogether.

Insurers are particularly concerned about applicants for individual insurance who seek to purchase

coverage because they are aware of a medical

problem that is not yet evident to the underwriter.

Such applicants pose a financial threat to the insurer,

and the situation is referred to as ‘‘adverse selection’ or ‘‘antiselection’ (of an insurer by high-risk

applicants). It refers to the situation where, in the

absence of any controls, persons who seek to obtain

insurance will tend to be those who will use it

most—that is, those with a greater than average

probability of loss to the insurer. Insurers’ ability to

accept applicants and their rating structure are

influenced by the threat of adverse selection (16).

The potential for adverse selection is most relevant

for small group and individual insurance, because

large groups tend to have an even distribution of

low- and high-risk individuals.

The Medical Information Bureau and Individual

Health Insurance

In 1902, a group of 15 life insurance companies

established the Medical Information Bureau (MIB).

Now located in Westwood, MA, MIB strives to

discourage fraud when companies are called on to

write insurance for applicants with conditions significant to longevity or insurability. MIB acts as a

medical information clearinghouse where member

companies can determine if an applicant for health

or life insurance has previously been denied coverage for medical reasons. About 750 U.S. and

Canadian life insurance companies at 1,150 locations belong to MIB (18). BC/BS companies are not

members of MIB, and therefore do not use its data

(4).

Although MIB was setup by and for life insurance

companies, a member can also access MIB for health

or disability insurance purposes if the member sells

those products. Perhaps more importantly, information about persons applying for individual health

insurance through an MIB member company can be

entered into MIB.

Applications for individual insurance-health,

life, or disability---carry an explanation about MIB.

If the insurance company finds something in an

applicant’s history that could affect longevity, the

member company must file a report with MIB about

the applicant’s insurability. The potential insurer

also may request an MIB check to see if past reports

about the applicant have been filed by other companies; MIB makes about 22 million such checks each

year. MIB’s reports alert a potential insurer to

omissions or misrepresentation of facts by an

applicant. In principle, an applicant can refuse to

allow his or her information to be communicated to

MIB. The penalty to the applicant, however, typically means refusal by the insurance company to

process the application.

MIB enters approximately 3 million coded records a year and has information on about 15 million

persons in the United States (6). Information about

applicants is encoded into a broad-based set of 210

medical categories and 5 nonmedica1 codes (e.g.,

aviation, hazardous sport) at the time an individual

applies for medically underwritten life, health, or

disability insurance from a member company. Not

all information entered into MIB is negative information about an applicant, as normal results of tests

are also submitted to MIB. For example, if an

applicant has a previous record for high blood

pressure, an entry might be made at a later date

reflecting a normal blood pressure reading. Insurance claims made by individuals are not a source of

records and codes for MIB.

MIB codes include a few for classifying genetic

diseases. A specific category exists for CF and a

broad category also exists for family histories of

hereditary disease. Currently, MIB has no plans for

expanding genetic disease categories to classify

information that could become available from new

genetic tests (6). Coded information on an applicant

is released to authorized personnel at the member
Chapter 7---Fnancing ● 175

company requesting the information through computer terminals dedicated exclusively to MIB activities.

Any individual can inquire whether MIB retains

a record on him or her. Individuals can inspect and

seek correction of their own records. On average,

19,000 people request disclosure annually, and

about 400 make corrections to their records. MIB

retains records on an individual for 7 years; if no

additional applications or inquiries come to MIB on

a person after that period of time, the record is

purged.

MIB emphasizes that its reports are not used as the

basis for a decision to reject an application or to

increase the cost of insurance premiums ( 18). Actual

underwriting decisions are based on information

from the applicant and from medical professionals,

hospital records, and laboratory results. In 12 States

it is illegal under the National Association of

Insurance Commissioners Insurance Information

and Privacy Protection Model Act to make underwriting decisions solely on the content of an MIB

record; the act also is adhered to by some insurers in

States that have not enacted it. Another deterrent to

using MIB codes to deny coverage: Insurers must

disclose the basis for an adverse underwriting

decision under the Federal Fair Credit Reporting Act

(Public Law 101-50).

REGULATION AN D

UNDERWRITIN G

Regulation of insurance in the United States is

largely State-based, although some Federal laws

apply, Within State laws, private insurers have some

discretion in determining insurance coverage and

how the costs will be distributed. For individual and

medically underwritten groups, how much a policy

costs, what type of coverage is available, and even

whether insurance can be bought at all are determined. in large part, by how a group or individual is

classified by insurers—i.e., rating, coverage, and

underwriting decisions.

Regulation of Insuring Entities

The McCarran-Ferguson Act of 1945 (Public Law

79-15) accords States the principal regulatory responsibilities with regard to the business of insurance, although some Federal laws (e. g., the Employee Retirement Income Security Act, or ERISA)

affect health benefit plans, particularly group plans.

Besides ERISA, the Federal tax code, through such

things as the exclusion of employer contributions for

health benefits from the taxable income of workers,

has an important impact on health insurance.

All 50 States and the District of Columbia have

insurance laws that require insurers to meet a variety

of financial and other requirements in order to obtain

a license to do business. These laws do not apply to

self-funded plans. The exact requirements vary

widely from State to State, but ordinarily stipulate

certain amounts of financial resources needed to

establish solvency as an insurer. BC/BS plans are

treated somewhat differently. Although they do not

have to adhere to State commercial insurance law,

they are subject to a rate-making process that does

not generally apply to commercial insurers.

Regulation of Insurance Contracts

All States require that individual health insurance

policy forms be filed with the appropriate regulatory

authority before being used. Some States require

filing and approval of premium rates for new

business as well as for renewal rate changes for

individual coverage. Most States also require similar

filings of group insurance contracts. Insurance laws

generally authorize a State insurance commissioner

(or comparable authority) to disapprove policies if

they contain unjust, unfair, inequitable, misleading,

or deceptive provisions. Many States also permit

their regulators to disapprove contracts on the

grounds that the benefits provided are unreasonable

in relation to the premium charged. Similar to the

policies directed at commercial insurers, many

BC/BS plans are required to obtain prior approval of

individual subscriber rate schedules.

Certain types of practices in issuing, continuing,

or canceling insurance polices are also prohibited

and monitored by States. Certain factors can be

barred from use in making underwriting decisions

for individual coverages. Even though rating classification schemes must be submitted to State insurance authorities for review, insurers are not required

(as they are with rating) to submit the criteria used

in underwriting to regulatory authorities (35), and

little empirical work on what State regulators

actually do in reviewing rating classifications is

available (26).
176 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Underwriting

Underwriting is the process by which an insurer

determines whether and on what basis it will accept

an application for insurance. Evaluating whether an

insurance applicant will be covered on a standard or

substandard basis---or not at all-is called risk

classification. Because of potentially large differences in the health status and potential risks presented of individual applicants, insurers evaluate

individuals using criteria different from those for

groups. Individuals generally are placed in classes

with about the same expectation of loss. Those with

higher than average risks might be accepted, but

under special conditions. Seventy-three percent of

applicants for individual policies from commercial

insurers are classified as standard (26). Those with

the highest expectation of loss are declined and

deemed uninsurable, except in some States where

BC/BS is required to accept all applicants (i.e., open

enrollment periods are required).

OTA SURVEY OF

HEALTH INSURERS

Although genetic tests and information are important to companies that offer disability and life

insurance (box 7-C), the 1991 OTA survey focused

on health insurance. Specifically, OTA conducted a

survey in 1991 of the commercial insurers, BC/BS

plans, and largest HMOs that write individual health

insurance policies or medically underwritten groups

to assess their practices and attitudes toward genetic

tests. Complete data from the survey, as well as

details about its methodology, are presented elsewhere (31). This section summarizes those findings

most pertinent to carrier screening for CF.

Demographics of the Survey Population

OTA’s survey population was derived from three

sources: a Health Insurance Association of America

(HIAA) database of member companies that offer

individual health coverage, the BC/BS Association

directory (3), and the Group Health Association of

America 1991 National Directory of HMOs (11).

Again, third-party payers’ policies and attitudes for

two particular populations were examined:

Individuals who seek insurance independently

and without any association with an employer or

membership group of any kind.

Medically underwritten groups---those groups whose

members must be medically underwritten.

Members of these populations are required by

insurers to undergo diagnostic tests or physical

examination before a policy will be issued. Some

large group policies might require tests or physical

examinations for cases of late applicants (i.e.,

employees who are eligible for group health insurance but choose not to sign up until after the normal

enrollment period when they know they will soon

Box 7-C—Life Insurance and Cystic Fibrosis

Life insurance does not provide access to health care, and the interaction of genetic tests with the life insurance

industry could differ considerably from that with the health insurance industry. In the United States, about 156

million people are covered by some type of life insurance. For those covered under group plans as part of employee

benefit packages, them is typically no medical testing or screening. For those who obtain individual life insurance,

however, some medical screening invariably accompanies an application, and its thoroughness usually reflects the

amount of coverage being sought. Companies reject about 3 percent of all applications for life insurance.

Life insurance generally is unavailable for individuals with cystic fibrosis (CF)-hence the current availability

of DNA-based assays has no impact on life insurance for people with CF. Similarly, since CF carrier status does

not affeet life expectancy, being identified as a carrier should have no bearing on access to life insurance.

Nevertheless, life insurance considerations in the context of CF carrier screening arise because of concerns about

the effect other DNA tests could have, generally. Thus, while identifying CF carrier status represents a case with

no risk of premature mortality related to that status (and having CF represents a case where an obvious risk of

premature mortality would preclude life insurance), other genetic screening that could occur in the future---e. g., for

breast or colon cancer-could influence the type and cost of life insurance coverage available to an affected

individual.

SOURCE: Office of Technology Assessment, 1992, based on ArnericanCouncil of Life Insurance, 1990 Life lnsuranceFactBook (Washington

DC: American Council of Life Insurance, 1990); and R. Bier, American Council of Life Insurance, ‘Questions and Answers: Genetic

Information and Insurance,” June 1990.
Chapter 7-Financing ● 177

Table 7-2—Number of People Insured by OTA Survey Respondents

Commercial insurers BC/BS plans HMOs

Individual policies Total: 2.0 million 1.7 million 306,861

Individual respondent: Range: 171 to 240,000 Range: 1,500 to 690,559 Range: 350 to 258,945

Medically underwritten Total: 2.3 million 2.4 million 4.0 million

group policies Individua/ respondent: Range: 1,000 to 382,000 Range: 1,039 to 1,592,000 Range: 1,501 to 2 million

SOURCE: Office of Technology Assessment, 1992.

have expenses), but this survey does not encompass

such cases. Thus, results from OTA’s survey apply

to the 12.7 million people who have individual or

medically underwritten group coverage provided

through survey respondents (table 7-2).2

Commercial Health Insurers

In the United States, approximately 1,250 forprofit companies are in the business of writing health

insurance policies (15). Increasingly, however, few

commercial health insurers write policies for individuals or medically underwritten groups-the focus

of OTA’s survey. The OTA survey was sent to 225

health insurers that had recently offered individual

coverage, as identified by the HIAA, and OTA

received responses from 132 commercial health

insurers (59 percent response rate). The list OTA

obtained was 4 years old, and in that time period well

over half of those companies had stopped offering

individual coverage (22), which is confined by the

81 commercial insurance companies responding that

they no longer wrote individual or medically underwritten group policies. Fifty-one commercial insurers responding to the OTA survey said they write

individual or medically underwritten group contracts. Of these respondents, 29 companies offer

individual coverage and 37 companies offer medically underwritten group policies. Fifteen companies offer both types of policies.

Blue Cross/Blue Shield Plans

Both the chief underwriters and the chief medical

directors for 72 of the 73 BC/BS plans were

surveyed. (Puerto Rico’s plan was excluded.) Twentynine chief underwriters completed a survey (40

percent response rate), as did 18 chief medical

directors (25 percent response rate). Of the 29

BC/BS plans represented by the chief underwriters,

25 write individual policies; 21 of 29 write medically underwritten group contracts. To represent a

larger pool of plans and because a number of

underwriters specified that their survey was a joint

underwriter/medical director response, only data

from the chief underwriters’ survey are used in this

chapter to describe BC/BS responses. Complete data

are presented elsewhere (31 ).

Health Maintenance Organizations

OTA sent surveys to the 50 largest local and

national HMOs, as well as a sample of 28 plans that

were the largest HMO within a State or the largest by

HMO model type. (Four HMO model types exist:

the staff model plan, group model plan, network

model plan, and independent practice association

model plan.) Forty-three surveys were returned (55

percent response rate); 20 of the responding HMOs

offered policies neither to individuals nor medically

underwritten groups. Of the 23 HMOs responding

that do offer such coverage, 11 HMOs accept

individuals and 20 medically underwrite groups.

General Attitudes Towards Genetic Tests

OTA’s survey findings indicate that insurers

generally believe that it is fair for them to use genetic

tests to identify those at increased risk of disease,

and that they should decide how to use that

information in risk classification (table 7-3). A

majority of medical directors from commercial

insurers (34 respondents, 67 percent) said they

“agree strongly’ or “agree somewhat” with the

statement that ‘ ‘it’s fair for insurers to use genetic

tests to identify individuals with increased risk of

disease’ 15 disagree to some extent (30 percent).

Similar responses were obtained from survey respondents from BC/BS plans and HMOs (table 7-3).

Survey respondents were also asked whether ‘‘an

insurer should have the option of determining how

to use genetic information in determining risks. ’

Thirty-eight commercial respondents (74 percent)

Z Throughout the discussion m tlus chapter, ‘‘no response’ IS not reported in the text, but the percentages presented account for them, as indicated

in the tables.
178 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 7-3-General Attitudes of Insurers Toward Genetic Tests

Agree Agree Disagree Disagree

Statement Respondent strongly somewhat somewhat strongly No responsea

agreed strongly or somewhat with this statement; 12

respondents (28 percent) disagreed to some extent.

Responses from HMOs indicated similar sentiments: 17 medical directors (74 percent) agreed

strongly or somewhat compared to 4 (17 percent)

who disagreed somewhat. For BC/BS plans, 24

respondents (83 percent) agreed with the statement

to some extent, against 4 respondents (14 percent)

who disagreed somewhat (table 7-3).

As genetic tests become widely available, under

what conditions do insurers believe a negative

financial impact would occur for their company?

The majority of commercial insurers (30 respondents; 59 percent) said a negative financial impact

would not occur if genetic tests were, in general,

widely available to the medical/provider community. In contrast, 34 respondents from commercial

insurers (67 percent) thought a negative financial

impact would occur under such circumstances if

constraints were placed on insurers’ access to the

results. Forty-seven respondents (92 percent)

thought a negative impact would occur if there were

adverse claims or underwriting results due to adverse selection (table 7-4). Similar results were

obtained from the BC/BS and HMO survey respondents (31).

OTA found that no commercial insurer had

conducted an economic analysis of the costs and

benefits of carrier tests as part of applicant screening

or genetic tests as part of applicant screening. One

commercial company reported it had done an

analysis of the costs and benefits of carrier tests as

part of prenatal coverage, but 48 companies had not.

Similar data were found for both the BC/BS plans

and for the HMOs (table 7-5). It is clear that few

companies have considered genetic tests or services

in terms of the costs and benefits of coverage. It is a

particularly important finding that companies had

not done such an analysis of the costs and benefits

of using genetic tests for the purpose of applicant

screening. For reimbursement purposes, it is also

important to note that most insurers have not looked

Table 7-4-impact of Genetic Tests on Insurers

Question Respondent Yes No No ns e

a

Under what conditions would a

negative financial impact be likely

tooccur for your company (check

all that apply):

Widespread availability of

genetic tests to the medical

provider community.

Widespread availability of

genetic tests with constraints

on insurers’ access to

results.

Adverse claims or underwriting results from

antiselection.

Commercials

HMOs

BC/BS plans

Commercials

HMOs

BC/BS plans

Commercials

HMOs

BC/BS plans

19 (37%)

10 (44%)

7 (24%)

34 (670/o)

16 (70%)

17 (59%)

47 (92%)

18 (78%)

27 (93%)

apermntages may not add to 100 due to rounding.

SOURCE: Office of Technology Assessment, 1992,
Chapter 7---Financing ● 179

Table 7-5—Economic Analyses of Genetic Tests and Genetic Counseling by Insurers

Question Respondent Yes No No response”

Has your company ever conducted an economic analysis

of:

Carrier testing as part of

applicant screening?

Carrier testing as part of

prenatal coverage?

Genetic testing as part

of applicant screening?

Genetic counseling of

carriers who are covered?

aPer@ntages may not add to 100 due to rounding.

SOURCE: Office of Technology Assessment, 1992.

into the costs and benefits of providing carrier

screening or genetic counseling as part of a benefits

package.

REIMBURSEMENT FOR GENETI C

SERVICES—OTA SURVE Y

RESULT S

Will insurers pay for voluntary screening and

followup counseling? And will insurance companies

authorize payment for prenatal screening or testing

of newborn children? Answers to these questions

carry significant cost implications. They also will

likely affect the degree to which carrier screening for

CF becomes commonplace, since many people will

be unwilling to pay out-of-pocket costs for the

assays.

Insurance industry representatives assert that

companies will not pay for most genetic tests unless

they are ‘‘medically indicated. ’ Thus, many health

insurance companies do not pay for what they

consider to be ‘‘screening’ tests (28). Currently, the

trend is toward closer evaluation of tests’ medical

necessity before insurance companies agree to pay

for them. For example, a BC/BS task force evaluates

30 or 40 different procedures and devices each year

and shares the results with the 73 independent

BC/BS plans, each of which makes its own decisions

about reimbursement (4).

More broadly, an increasing number of health

insurance plans require that patients receive approval for procedures, including diagnostic tests,

before the company will reimburse the cost. As more

people become aware of carrier screening for CF,

insurance companies are likely to receive more

requests for reimbursement. In addition to uncertainty about reimbursement for the test, uncertainty

also exists as to who will pay for the genetic

counseling that must accompany CF carrier screening. Third-party insurers often have a policy of not

reimbursing for counseling unless performed by

physicians, which means the costs me reimbursed as

general medical consultation fees or absorbed as part

of costs on research grants (28).

From the perspective of the commercial laboratory that provides genetic tests to medical providers

and patients, the issue of reimbursement is crucial to

the level of their potential business--current and

future. Few efforts have been made to assess the

degree that CF carrier screening is being reimbursed

by insurers and self-funded companies, but some

individuals have been successful in obtaining reimbursement even in the absence of family history.

One private genetic service provider surveyed 66

patients about this issue in February 1991, and 27

responded (40 percent). After CF carrier screening,

each patient had been given a letter explaining the

CF carrier assay to submit with their claim. Thirdparty payers covered all costs of CF carrier screening for 11 of the 27 patients who responded; costs for

5 patients were covered in part and 11 received no

reimbursement. Three of the eleven patients who

received no reimbursement did not submit the letter

to their insurer (9). Two individuals who were
180 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

originally denied coverage appealed the decision

and received full coverage. All patients who were

partially covered had 80 percent coverage or had not

yet met their deductible, which is compatible with

CF carrier screening being treated as a compensable

procedure. While the survey data represent a small

sample size at one clinic, the information collected

shows that some patients have obtained reimbursement when CF mutation analysis is done for

screening purposes.

On balance, however, it appears that, for now, if

no medical indication for the test exists, a third-party

payor generally will not pay for the assay. However,

an appeal can usually be made and is sometimes

successful for CF carrier screening when the specifics of mutation frequencies are documented (2).

Nevertheless, lack of reimbursement is likely to

influence the number of individuals who opt to be

screened. Thus, the concept of medical necessity is

particularly important to CF carrier screening and

revolves around the issue of standards of care (ch. 5);

insurers are likely to continue refraining from

reimbursement for tests not judged to be customary

physician practice. If CF carrier screening becomes

commonplace, especially in the context of obstetric/

prenatal care, the current situation of third-party

payment for CF mutation assay could change.

To analyze the extent to which genetic tests and

services were being, or might be, reimbursed by

third-party payers, OTA collected data from three

populations: genetic counselors and nurses in genetics, health insurers, and State Medicaid directors.

Experiences of Genetic Counselors

and Nurses

In June 1991, members of the National Society of

Genetic Counselors and the International Society of

Nurses in Genetics who said they were currently in

clinical practice were asked about the health care

coverage of their patients (30). Approximately half

of the respondents (198 respondents, 51 percent)

reported that their patients have health care coverage

very often or always (defined as between 75 and 100

percent of their patients). However, 43 respondents

(11 percent) said that their patients sometimes or

seldom if ever had coverage (between O and 50

percent of their patients).

Survey respondents were asked to recount their

experience with reimbursement for various genetic

services they performed. For general genetic counseling services, 22 (5 percent) responded they

seldom if ever were covered, 56 (13 percent) said

they sometimes were covered, 53 (12 percent) said

they often were covered, 42 (10 percent) said they

very often were covered, and 67 (16 percent) said

they almost always were covered.

Where there was a positive family history for CF,

genetic counseling was reported to be seldom if ever

covered by 17 respondents (4 percent), sometimes

covered and often covered by 86 (20 percent), very

often covered by 26 (6 percent), and almost always

covered by 65 (15 percent) respondents. Where there

was no family history for CF, genetic counseling

was reported to be seldom if ever covered by 35

respondents (8 percent), sometimes or often covered

by 69 respondents (16 percent), very often covered

by 10 respondents (3 percent), and almost always

covered by 16 respondents (4 percent).

When asked if they knew of a patient’s insurance

claims for DNA analysis being rejected, 96 respondents (27 percent) said that they knew of such

denials. One respondent to OTA’s 1991 survey of

genetic counselors and nurse geneticists gave this

reason for the denial of a client’s claim:

In one family, the husband had an affected first

cousin. This insurance would not pay for his

screening because it is only a risk if the woman is a

carrier and that the father’s carrier status did not

affect the pregnancy.

It is clear in this case that the insurance company

falsely assumed that the father’s carrier status was

not relevant to the condition. At least two other

surveys were conducted recently that also dealt with

the issue of reimbursement for genetic screening

services (1,19). One of these found a majority of

respondents obtained full or partial reimbursement

for CF mutation analysis. Reimbursement was more

likely if a pregnancy was involved or when there was

a family history of CF (l).

Health Insurers’ Approaches

OTA’s survey of health insurers inquired whether

certain genetic tests or services-again, for individual and medically underwritten groups-are covered

‘‘at patient request’ (no family history, i.e., screening), ‘‘only if medically indicated’ (family history),

or “not covered. ’ No commercial company reimburses for CF carrier tests for screening purposes.

The survey also found that carrier tests for CF—as

well as Tay-Sachs and sickle cell (31)--are not
Chapter 7---Financing ● 181

covered for any reason by 12 of 29 commercial

insurers that offer individual coverage. Twelve

respondents (41 percent) cover CF carrier assays if

medically indicated. With respect to prenatal tests

for Cl?, about 41 percent (12 respondents) that write

individual policies reimburse for such tests when

medically indicated (table 7-6).

For the 37 commercial companies offering medically underwritten group policies, carrier tests for

CF (and, again, sickle cellorTay-Sachs(31)) are not

covered by any company when done solely at patient

request. CF mutation analysis is covered by 24 of 37

companies if medically indicated. Ten companies

offering medically underwritten group coverage do

not cover any of the carrier or prenatal tests in the

OTA survey. Sixty-two percent of companies (23

respondents) that offer medically underwritten group

policies cover prenatal tests for CF (table 7-6).

Two of 25 BC/BS plans offering individual

coverage would reimburse CF carrier screening at

patient request. Sixteen of these BC/BS plans (64

percent) cover them if they are medically indicated

and seven do not cover them. For prenatal tests for

CF, 3 of these companies cover them at a patient’s

request, 19 if medically indicated, and 3 not at all. Of

21 BC/BS plans offering coverage to medically

underwritten groups, CF carrier screening is covered

at patient request by 2 companies (10 percent), only

if medically indicated by 11 companies (52 percent),

and not at all by 8 companies (38 percent) (table

7-6). Data for reimbursement for prenatal CF tests by

BC/BS companies that medically underwrite groups

are also presented in table 7-6.

Of the 11 HMOs that offer health insurance under

individual policies, 1 respondent (9 percent) covers

CF carrier tests at patients’ requests and 7 HMOs (64

percent) reimburse for them if medically indicated.

For the 20 HMOs that offer medically underwritten

group contracts, 1 HMO (5 percent) covers CF

carrier tests at patients’ request, 13 respondents (45

percent) reimburse for them if medically indicated,

and 2 (10 percent) do not cover them at all. Table 7-6

presents these results as well as how HMOs cover

prenatal tests for CF.

OTA’s survey results reveal that carrier and

prenatal tests often are not covered under individual

and medically underwritten group policies unless

they are medically necessary-i. e., a family history

exists. Such lack of reimbursement could have a

Table 7-6---Reimbursement for Cystic Fibrosis Carrier Tests and Genetic Counseling

Question: Do your standard individual policies and medically undewritten policies provide coverage for:

At patient Medically Not No

Respondent request indicated only covered response.
182 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

significant impact on the ultimate utilization of CF

mutation analysis.

OTA found that genetic counseling was not

covered by 18 of 29 commercial companies offering

individual coverage and 17 of 37 offering medically

underwritten group coverage. Six insurance companies offering individual policies and 16 that medically underwrite groups cover genetic counseling

only if it is medically indicated. Two companies

offering each type of coverage will reimburse for

genetic counseling at the patient’s request (table

7-6). Similar results for BC/BS plans and HMOs are

also presented in table 7-6.

Finally, respondents were asked to indicate whether

they agreed or disagreed with the following scenario:

Through prior genetic testing, the husband is

known to be a carrier for CF. Before having children,

the wife seeks genetic testing for CF. The insurance

company declines to pay for the testing, since there

is no history of CF in her family.

For commercial insurers, 21 medical directors (41

percent) agreed strongly or somewhat. Twenty-nine

respondents (47 percent) disagreed somewhat or

strongly with this scenario. For respondents from

BC/BS plans, 12 agreed strongly or somewhat (41

percent) and 15 disagreed strongly or somewhat (52

percent). Four respondents from HMOs (17 percent)

agree somewhat compared to 17 who disagreed

somewhat or strongly (74 percent). These results

indicate that insurers are split in their attitudes (or in

their understanding of genetics) towards financing

CF carrier screening as a part of reproductive

decisionmaking.

Medicaid Reimbursement

For some low income citizens, Medicaid provides

access to genetic tests and genetic counseling.

Medicaid reimbursement for genetics and pregnancyrelated services has been reported to vary from State

to State (34). To examine the current state of such

reimbursement, OTA surveyed directors of State

Medicaid programs in June 1991 to assess which of

seven services-amniocentesis, ultrasound, chorionic villus sampling (CVS), maternal serum alphafetoprotein (MSAFP) tests, DNA analysis, chromosomal analysis, and genetic counseling-were covered. OTA also asked for information about reimbursement amounts for each service.

Respondents were asked to indicate if their State

guidelines stipulated whether a procedure was

‘‘covered, “not covered, ” “coverage based on

individual consideration, ’ or ‘‘unknown. There

was no attempt to determine how completely these

guidelines were followed by each State, and there

have been reports that people have experienced

difficulties in getting any Medicaid reimbursement

for the types of services OTA inquired about (29). In

total, 47 States and the District of Columbia

responded (94 percent response rate). Two States

responded to OTA’s survey, but are not included in

this analysis. Arizona’s program differs from all

other States, and OTA could not obtain comparable

data for it. Connecticut returned a survey, but said

budget restraints precluded it from completing the

survey.

State coverage of genetic procedures clearly

varies (tables 7-7, 7-8). Of the 46 States3 in the

analysis, 45 cover amniocentesis, with an average

reimbursement of $59.32. Fetal ultrasound is covered in 44 of 46 States, with 2 States covering it only

by individual consideration. The average reimbursement for fetal ultrasound is $83.13. CVS is covered

by 31 States (67 percent) and not covered in 10

States (22 percent), with 1 State reporting unknown

coverage and 4 States reporting individual consideration only. The average reimbursement for CVS is

$145.90. MSAFP testing is covered in 44 States and

by individual consideration in 2 States. Average

reimbursement for MSAFP is $21.76.

DNA analysis is covered by 26 States (57 percent)

and not covered in 6 States (13 percent), with

unknown coverage in 8 States (17 percent) and 6

States (13 percent) covering it based on individual

consideration. Average reported reimbursement for

DNA analysis is $33.39. Chromosome analysis,

from amniotic fluid or chorionic villus, is covered by

41 States (89 percent), not covered by 1 State, with

4 States (9 percent) reporting individual consideration only. Average reimbursement for chromosome

analysis is $235.68.

Whether the State covered genetic counseling

clearly posed the most difficult question for Medicaid program directors. A substantial percentage

indicated that if the service were coded as an office

s Hereinafter, “States” refers to the 45 States and the District of Columbia that completed a questionnairee used in OTA’S analysis.

.
Chapter 7---Financing . 183

Table 7-7—Medicaid Reimbursement for Genetic Procedures By State

Chorionic Maternal serum DNA Chromosome

State

Genetic

Amniocentesis Ultrasound villus sampling alpha-fetoprotein analysis analysis counseling

$24.34

31.00

$199.99

270.00

Not covered

Covered if part of

office visit

29.50

Not covered

275.21

273.18

Not covered

$200.56 complete

133.40 interim

100.28 followup

29.25 275.12 Not covered

Delaware. . . . . . . .

District of

Columbia. . . . . .

Florida. . . . . . . . . .

Georgia. . . . . . . . .

Hawaii. . . . . . . . . .

Did not respond.

41.00 100.71

23.00

107.00

75.60

15.87

24.50

6.85

23.52

26.55

24.41

b

22.11

20.25

24.41b

15.70

15.00

27.26

16.73

20.60

25.28

6.15

24.41

42.30

42.89-55.76

14.00

10.20

23.41

6.50

20.80

21.73

24.41

24.41

22.94

20.00

6.20

24.41

24.98

23.77

20.87

25.00

25.00

24.38

24.98

24.13

22.00

?

14.50

Not covered

?

80.00

243.50

28.69

164.5@

137.00

80.00

81.25

Idaho. ... . . . . . .

Illinois. . . . . . . . . .

Indiana. ., . . . . . .

Iowa. . . . . . . . . . .

Kansas. . . . . . . . .

Kentucky. . . . . . . .

Louisiana. . . .

Maine. . . . . . . . .

41.90

59.95

b

56.5 8

100.00

75.00-100.00

39.48

23.00

88.90

70.65

b

84.17

120.00

97.50-130.00

80,00

25.30-59.40

281.83

87.10

b

278.69

Not covered

268.94b

275.21

251.00

Maryland. . . . . . . .

Massachusetts. . .

31.00

49.43

56.00

92.00

31.00

481.07

54.00

24.76

215.25

225.73

Michigan. . . . . . . . 36.80 66.12 358.17 ? 167.31

Minnesota. . . . . . . 55.00 70.00 153.00 30.57 278.71

Mississippi. . . . . .

Missouri. . . . . . . . .

Montana. . . . . . .

41.90

25.00

51.91

69.30

65.00

68.68

Not covered

Not covered

65.2% of charges

Not covered

16.43

?’

260.56

150.00

309.79

Nebraska. . . . . . . .

Nevada. . . . . . . . .

New Hampshire. . .

New Jersey. . . . . .

New Mexico. . . . . .

New York. . . . . . . .

North Carolina. . . .

North Dakota. . . . .

Ohio. . . . . . . . . . .

Oklahoma. . . . . . .

Oregon, . . . . .

Did not respond.

69.70

25.00

37.00

59.60

20.00

119.20

39.28

75.00-98.00

59.50

44.48

Covereda

b

Not covered

?

Covereda

Not covered

52.20

250.00-402.00

Not covered

38.05

152.36

64.00

55.00

52.87

55.00

73.44b

109.93

95.77-102.65

92.70

74.82

Pennsylvania. ... 50.00 97,50 59.00 14.50-30.80 275.20

Rhode Island. . . . .

South Carolina. . .

South Dakota. . .

Did not respond.

31.80

63.00

66.00

100.00

28.50

29.50

300.00

275.21

Not covered

?

Tennessee. . .

Texas, . . . . . . .

57.00-60.00

81.22

51.00-88.00

116.41

109.68

?

275.21

200.00

Utah. . . . . . . . . . . 46.45 47.29 111.60 11.86

Vermont. .

Virginia. ... ., . .

22.00

110.00

75.00

90.00

Not covered

66.00

Not covered

10.50

400.00

135.00

251.91

275.20

Washington. . .

West Virginia. . . . .

31.54

43.00

61,10

36.00

281.47

198.00

Wisconsin. . . . . . .

Wyoming. . . . . . .

47,64

50.00

115.68

127.95
184 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

SOURCE: Office of Technology Assessment, 1992.

visit or consultation, it might be covered; in such

cases, however, the service of genetic counseling is

hidden in a general visit code. Eleven States (24

percent) reported covering genetic counseling; 11

(24 percent) reported covering it only if part of an

office visit or consultation; 19 States (41 percent) do

not cover genetic counseling, 2 States cover it by

individual consideration, and 3 States (7 percent)

reported unknown coverage. The average reimbursement amount, in large measure, reflects the

range of reimbursements for different levels of office

visits. As such, the average amount given ($68.87)

cannot be viewed as accurate for genetic counseling

services only. It should also be noted that ‘‘family

DNA testing” is covered in some States (e.g., New

York).

In addition to finding that some States do not

cover certain services, the survey indicates the

amounts reimbursed by States that do pay fall well

short of charges for the procedures (5,23) (ch. 9).

Hence, genetic service providers that accept Medicaid patients must subsidize the costs.

SUMMARY AND CONCLUSIONS

Because the U.S. insurance industry is not homogeneous in its composition and policies, interest in

new technologies (e.g., CF carrier screening) will

vary according to both the type of insuring entity and

the specific company or plan involved. The majority

of the insured U.S. population obtains health insurance through the workplace under group policies.

Such policies do not require diagnostic tests or

physical exarninations. Some Americans, however,

obtain health insurance through medically underwritten group policies or obtain it on an individual

basis. These individuals typically undergo risk

classification and might pay higher rates. Yet little

data exist on how commercial insurers, Blue Cross

and Blue Shield plans, and health maintenance

organizations factor genetic tests in the risk classification process. Chapter 8 reports OTA survey data

related to this issue.

How insurers view genetic tests, generically,

might affect their utilization. OTA’s 1991 survey of

commercial insurers, BC/BS plans, and HMOs that

offer individual policies or medically underwrite

groups sheds some light on how these populations

view genetic tests, generally, and CF carrier tests,

specifically. Clearly, they want the option of determining how to use genetic tests in determining g risks.

OTA’s survey also found that insurers generally

agree that it is fair for them to use genetic tests to

identify persons with increased risk of disease.

Finally, the issue of who pays for CF carrier tests,

prenatal tests for CF, and genetic counseling is

important to the frequency at which people will opt

for CF carrier screening. OTA survey results indicate that the costs of carrier tests or prenatal tests for

CF (as well as sickle cell anemia and Tay-Sachs) are

rarely covered by an insurer when carried out at the

patient’s request. Insurers either covered those costs

when medically indicated (family history) or not at

all. With respect to public financing for genetic tests,

OTA surveyed State Medicaid directors to determine which services were covered and at what

levels. Medicaid reimbursement for genetic services

varies widely from State to State and does not

approach full reimbursement of the actual amount

charged for the service.

1.

2.

3.

4.

5.

CHAPTER 7 REFERENCE S

Bemha.rdt, B. A., and Eierman, L. A., “Reimbursement for Cystic Fibrosis (CF) DNA Testing, ”

submitted abstract, American Society of Human

Genetics, 42nd Annual Meeting, June 1992.

Bemsten, C., Vivigen, Inc., Santa Fe, NM, personal

communication, April 1991.

Blue Cross and Blue Shield Association Directory

(Chicago, IL: Blue Cross and Blue Shield Association, 1990).

Conway, L., Blue Cross and Blue Shield Association,

Washington, DC, personal communications, February 1991, December 1991.

Davis, J. G., New York Hospital, New York, ~,

personal communication, March 1992.
Chapter 8

Discrimination Issues
Contents

Page

STIGMATIZATION AND CARRIER STATUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

Empirical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .191

Screening Without Increasing Stigma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

HEALTH CARE COVERAGE ... .*. *.. ..*. ... ..**. .. * o . . . . . . . . . . . . . . . . . . . . . . . . . . 192

Insurers’ Attitudes Toward Genetic Risk Factors: OTA Survey Results . . . . . . . . . . . . 193

Access to Health Insurance After Genetic Tests: OTA Survey Results . . . . . . . . . . . . . 199

GENETICS, DISCRIMINATION, AND U.S. LAW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

State Statutes and Hereditary Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

The Americans With Disabilities Act of 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

CHAPTER 8 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .207

Boxes

8-A. Bree Walker Lampley and Preventing Versus Allowing Genetic Disability . . . . . . 191

8-B. Ethics, Genetics, and Health Insurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

8-C. McGann v. H & H Music Co. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

8-D. The California Hereditary Disorders Act of 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

Figure

8-1. Genetics and the Americans With Disabilities Act of 1990 . . . . . . . . . . . . . . . . . . . . . 205

Tables

8-1. Genetic Information as Medical Information or Preexisting Conditions . . . . . . . . . . 195

8-2. Medical History, Genetic Factors, and Insurability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

8-3. Projected Use of Genetic Tests by Insurers in 5 and 10 Years . . . . . . . . . . . . . . . . . . 198

8-4. Projected Use of Genetic Information by Insurers in 5 and 10 Years . . . . . . . . . . . . 199

8-5. Difficulties in Obtaining or Retaining Health Insurance After Genetic Tests . . . . . 200

8-6. Case Descriptions of Genetic Testing and Health Insurance Problems . . . . . . . . . . . 200
Chapter 7-Financing . 185

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19

20.

21,

Day, N., Medical Information Bureau, Inc.,

Westwood, MA, personal communications, September 1991, December 1991.

DiCarlo, S., and Gabel, J., “Conventional Health

Insurance: A Decade Later,’ Health Care Financing

Review 10(3):77-90, 1989.

Gallagher, T., National Association of Lnsurance

Commissioners, “Health Insurance Rating,” testimony before the Subcommittee on Commerce, Consumer Protection and Competitiveness, Committee

on Energy and Commerce, House of Representatives,

U.S. Congress, Apr. 30, 1991.

Genetics & IVF Institute, Fairfax, VA, “Survey of

Insurance Coverage of Cystic Fibrosis Testing, ”

personal communication, May 1991.

Group Health Association of America, Employers,

HMOS, and Dual Choice (Washington, DC: Group

Health Association of America, 1984).

Group Health Association of America, 1991 National

Directory (Washington, DC: Group Health Association of America, 1991).

Halifax, J., ‘‘Bill Would Close Health Insurance Pool

to Newcomers,” Associated Press, Apr. 16, 1991.

Hall, M., “The Purpose of Reforms in the SmallGroup Market,’ New England Journal of Medicine

326:565-570, 1992.

Health Lnsurance Association of America, Source

Book of Health Insurance Data 1991 (Washington,

DC: Health Insurance Association of America, 1991).

Iglehart, J.K., ”The American Health Care System—

Private Insurance,” New England Journal of Medicine 326: 1715-1720, 1992.

Jest, D, C., Blue Cross and Blue Shield Association,

‘‘Health Insurance Rating Practices, ’ hearing before

the Subcommittee on Commerce, Consumer Protection and Competitiveness, Committee on Energy and

Commerce, House of Representatives, U.S. Congress, Apr. 30, 1991.

Kass, N. E., “The Ethical, bgal and Social Issues

Concerning the Use of Genetic Tests by Insurers:

Toward the Development of Appropriate Public

Policy,’ manuscript prepared for the NIII/DOE

Ethical, hgal, and Social Issues Working Group,

November 1990.

Medical Information Bureau, Inc., A Consumer’s

Guide (Westwood, MA: Medical Information Bureau, Inc., 1991).

O’Connor, K., letter to the editor, Perspectives in

Genetic Counseling 13(2):10, 1991.

Payne, J., Health Insurance Association of America,

Washington, DC, personal communication, December 1991.

Pokorski, R., North American Reassurance Comp.,

Westport, ~, personal communication, February

1991.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

Raymond, H., Health Insurance Association of America, Washington, DC, personal communication, December 1991.

Schulman, J. D., Genetics & IVF Institute, Fairfax,

VA, personal communication, March 1992.

U.S. Congress, Congressional Research Service,

Health Care Financing and Health Insurance: A

Glossary of Terms (Washington, DC: Congressional

Research Service, August 1988).

U.S. Congress, Congressional Research Semice,

Health Insurance, IB900005 (Washington, DC: Congressional Research Service, May 1991).

U.S. Congress, General Accounting Office, Issues

and Needed Improvements in State Regulation of the

Insurance Business, GAO/FAD-79-72 (Gaithersburg, MD: U.S. General Accounting Office, October

1979).

U.S. Congress, Office of Technology Assessment,

Medical Testing and Health Insurance, OTA-H-384

(Washington, DC: U.S. Government Printing Office,

August 1988).

U.S. Congress, Office of Technology Assessment,

“Cystic Fibrosis, Genetic Screening, and Insurance, ’ transcript of workshop proceedings, Feb. 1,

1991.

U.S. Congress, Office of Technology Assessment,

“Cystic Fibrosis, Genetic Screening, and ERISA,”

transcript of workshop proceedings, Aug. 6, 1991.

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and Generic Screening: Policies,

Practices, and Attitudes of Genetic CounselorsResul?s of a Sun’ey, OTA-BP-BA-97 (Washington,

DC: U.S. Government Printing Office, forthcoming

1992).

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and Genetic Screening: Policies,

Practices, and Attitudes of Health Insurertiesults

of a Survey, OTA-BP-BA-98 (Washington, DC: U.S.

Government Printing Office, forthcoming 1992).

U.S. Department of Health and Human Services,

Public Health Service, National Center for Health

Statistics, Characteristi~s of Persons With and Without Health Care Coverage: United States, 1989, No.

201, June 1991.

Vranka, L. A., “Defining the Contours of ERISA

Preemption of State Insurance Regulation: Making

Employee Benefit Plan Regulation an Exclusively

Federal Concern, ’ Vanderbilt LuwRmi*’ 42(579):607-

638, 1989.

Weiner, J., and Bemhardt, B. A., “A Survey of State

Medicaid Policies for Coverage of Abortion and

Prenatal Diagnostic Procedures, ’ American Journal

of Public Health 90:717-720, 1990.

Wortham, L., “Insurance Classification: Too Important To Be IA? to the Mtmries,’ Uni}’erszfy of

Michigan Journal of Law Reform 19:349-423, 1986.
Chapter 8

Discrimination Issues

dis•crim•i•na•tion/dis-krim-a-niã-shan/ n differential treatment or favor with a prejudiced outlook or action.

stigŽmaŽtiŽzaŽtion/stig-ma-to-zã-shan/ n branding, marking, or discrediting because of a particular

characteristic.

Stigmatization of, or discrimination against, persons with certain diseases is not unique to genetic

conditions. Persons with certain infectious diseases

(e.g., leprosy, tuberculosis, or AIDS) have often

borne the brunt of social ostracism, as have people

with conditions such as cancer or schizophrenia (for

which genetic components are now known to exist).

As technologies for predicting genetic disorders

expand, so do concerns about behavior toward

people who have such conditions, or who are carriers

for them.

The primary effect of any screening is to provide

information (18), but how will the information be

used? What is ‘‘genetic discrimination, ’ and will it

increase (27,33,48)? Will the new knowledge elucidated through the Human Genome Project positively

or negatively affect how Americans obtain or retain

health care coverage?

This chapter examines aspects of discrimination

from several perspectives: societal stigmatization,

access to health care coverage, insurers’ views

toward genetic information, and genetics and new

Federal antidiscrimination law (i.e., the Americans

With Disabilities Act of 1990 (ADA); Public Law

101-336; 42 U.S.C. 12101 et seq.).l For some areas,

the discussion is limited to carrier status. In others,

the analysis encompasses the broader issue of the

role genetic information and tests—whether to

reveal carrier status or diagnose illness-play in

discrimination issues.

STIGMATIZATION AN D

CARRIER STATU S

Increased knowledge about human genetics challenges existing public perceptions of “genetic

normalcy. In his or her genome, each person

harbors stretches of DNA that silently code for

recessive, lethal, or debilitating genetic disorders or

that predispose-with or without certain environmental factors—future illness. As the Human

Genome Project progresses, the capacity to reveal

these silent genes will increase. What will the social

and psychological effect of knowing such information be to an individual? Will carriers be viewed as

flawed-by themselves or others-or as blamewortthy for having children despite identified genetic

risks? Because genetic diseases sometimes cluster in

ethnic or racial groups, will the potential for

discrirnination and stigmatization be compounded

(27,38)? Public misinformation, for example, can

lead to a ‘‘courtesy stigma’ applied to those

afffiated only by common ancestry to the stigmatized individuals (25,38).

Some express concern that routine carrier screening for cystic fibrosis (CF) (or other disorders) might

be viewed as a tacit acknowledgment that the birth

of children with genetic conditions should be

avoided. They express concern that if emphasis is

placed on preventing the births, less effort will be

made, or fewer funds allocated, to create a climate of

greater tolerance and social inclusion of people with

disabilities (3,63). Similarly, concern is raised that a

focus on prenatal CF carrier screening raises questions about further stigmatization of pregnant women

(41); one 1992 survey found 70 percent of respondents viewed all pregnant women as “people who

are acutely sick’ (44,52).

While some relationship exists between a characteristic’s visibility and the amount of stigma it

arouses (29,57), nonvisible characteristics (e.g.,

carrier status) are also stigmatized (25). Individuals

who reveal hidden differences often encounter

hostility, aversion, or discomfort (25). People with

epilepsy, for example, have been ostracized---even

in the absence of a visible seizure-when others

have found out about their condition (60, 1983).

Thus, because CF carrier status is not observable, the

condition could be less stigmatized than some

* The use of genetic monitoring and screening assays specitlcally in the workplace, and the broad array of legal implications arising from such use,

were discussed in an earlier OTA report (68). This chapter expands on developments since publication of that report. It focuses on the ADA and its

implications for employability of carriers or persons with genetic disease.

–189--
attributes, but some negative reactions might well

result from carrier idenitification.

In fact, stigmatization of carriers is likely to focus

on beliefs that it is irresponsible and immoral for

people who could transmit disability to their children to reproduce (box 8-A) (23,54). Embodied in

this notion is the view expressed by one philosopher

that: “If reproductive partners are informed they

both carry a dread disease such as Tay-Sachs or CF,

and even so conceive with the intention of bringing

every conceptus to birth, their supposed right to

reproduce becomes ethically invalid” (23).

While this sentiment represents one pole in the

gradient of views on reproductive decisionrnaking

and genetic information, it is not inconsistent with

the views of many Americans. A 1990 general

population survey found 39 percent said “every

woman who is pregnant should be tested to determine if the baby has any serious genetic defects. ’

Twenty-two percent responded that regardless of

what they would want for themselves, ‘‘a woman

should have an abortion if the baby has a serious

genetic defect,” with nearly 10 percent believing a

woman should be required by law to have an

abortion rather than have the government help pay

for the child’s care if the parents are poor (64).

How CF is viewed by the American populace

obviously will affect perceptions and potential

reproductive stigma associated with CF carriers.

Increased public awareness and education as screening becomes more common could reduce problems

of stigmatization of carriers, generally, with CF
Chapter 8---Discrimination Issues . 191

Box 8-A—Bree Walker Lampley and Preventing Versus Allowing Genetic Disability

In July 1991, Los Angeles radio talk show host Jane Norris launched a fiestorm of controversy when she

solicited listener comments on Los Angeles television anchorwoman Bree Walker Lampley’s pregnancy. Making

her disapproval clear, Norris said:

We’re going to talk about a woman in the news and I mean that literally. She’s a very beautiful, very pregnant

news anchor, and Bree Walker also has a very disfiguring disease. It’s called syndactyly [sic] and the disease is very

possibly going to be passed along to the child that she’s about to have. And our discussion this evening will be, is

that a fair thing to do? Is it fair to pass along a genetically disfiguring disease to your child?

Bree Walker Lampley has ectrodactyly, a genetic condition manifest as the absence of one or more fingers or

toes. It is an autosomal dominant disorder; hence her potential offspring have a 50-50 chance of inheriting

ectrodactyly. Norris’ show highlighted the public tension that exists over attitudes toward preventing genetic

disability, illness, and disease.

Some listeners agreed with Norris’ opinion against knowingly conceiving a child who would be at 1 in 2 risk

of “this deformity-webbed hands, . . .“ One caller stated she would “rather not be alive than have a disease like

that when it’s a 50-50 chance. ” Other callers compared her comments to racism and eugenic genocide: “. . this

tone of yours that just kind of smacks of eugenics and selective breeding. . . . Are you going to talk in the next hour

about whether poor women should have kids?”

The opinions offered illustrate the concern over the potential for discrimination or stigmatization as personal

knowledge of one’s genetic makeup increases. Shortly after the program aired, one disability rights activist pointed

out that the radio show reminded her of her discomfort with the Human Genome Project.

On August 28, 1991, Bree Walker Lampley delivered a healthy baby boy, who has ectrodactyly. In October

1991, arguing that a biased presentation with erroneous information was broadcast, Walker Lampley was joined by

her husband, several groups, and other individuals in filing a complaint with the Federal Communications

Commission (FCC), Norris and the radio station stand by their right to raise the issue and “have no regrets.” The

FCC rejected Walker Lampley’s complaint in February 1992, and no appal is planned.

SOURCE: Office of Technology Assessment 1992, based on Associated Press, ‘‘KC Rejects Anchorwoman’s Complaint Over Call-In Radio

Show, ” Feb. 14, 1992; J. Mathews, “The Debate Over Her Baby: Bree Walker Lampley Has a Deformity. Some People Think She

Shouldn’t Have Kids,” Washington Post, Oct. 20, 1991; and J. Seligmann “Whose Baby Is It Anyway?, ’’Newsweek, Oct. 28, 1991.

carrier screening serving as a model. Such awareness expressed attitudes of superiority (11). One survey,

and education might avert a case such as one

described by a respondent to OTA’s 1991 survey of

genetic counselors and nurses in genetics:

Carrier screening can be a loaded gun; just this

week one of our patients learned he was a carrier of

the DF508 mutation and his fiancee broke off their

engagement. Now not only has he been dealt the bad

news of being a carrier, his personal life is in a

shambles and we have spent a great deal of time

addressing his feelings of guilt, anger, and betrayal.

Empirical Studies

A few empirical studies addressing stigmatization

and carrier status have been conducted in the United

States, most in conjunction with Tay-Sachs screening during the 1970s ( 12-15,35; app. B). Data

indicate that the majority of carriers felt they were

not stigmatized, but one program found that 10

percent of noncarriers reported they would not marry

a carrier (14,15). A small percentage of noncarriers

conducted about 2 years after carriers were identified through Tay-Sachs screening, reported they and

their spouses were initially “upset” when they

learned the results, but that only a small minority

considered themselves adversely affected (1 1).

Little current data on stigmatization and genetics

exist; few are specific to CF. Research funded by the

National Center for Human Genome Research,

National Institutes of Health (NIH), however, is

under way (47). One pilot study on attitudes toward

CF carriers was recently conducted among high

school students in Montreal, Canada who had been

screened for DF508. In general, carriers expressed

positive views about their new awareness of carrier

status. Most (68 percent) would want their partner

tested, and 60 percent said if the partner were a

carrier, it would not affect the relationship. Sixtythree percent of persons negative for DF508 believed

there would be no harm to their self-image should

subsequent screening reveal they were actually
192 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

carriers of a non-DF508 CF mutation. The study is

only preliminary, however, with a small sample size.

Further, some speculate that social values and the

structure of Canada’s health care system might

render these data nontransferable to attitudes in the

United States (36), although others believe the

Canadian experience can be applied here (62).

Screening Without Increasing Stigma

Concern about stigmatization arising from widespread CF carrier screening does not necessarily

translate to unequivocal opposition by advocates for

individuals with disabilities. A coherent effort that

includes successful education and counseling could

offer CF carrier screening without stigmatizing

people with CF mutations as being disabled. Achieving this requires a commitment by health professionals and government that only those wanting to be

screened will be screened; that all who want

screening can have access to it; that results will

remain confidential; and that individuals will not be

coerced-overtly or covertly-into making any

particular reproductive decision following screening

(3,39).

Reducing perceived biases-so individuals can

autonomously access the data needed to make

informed choices about bearing children with CF—

is of paramount concern if widespread CF carrier

screening is to be viewed acceptable to those

concerned about disability rights and the potential

for stigmatization (3,13,55). Despite the commitment to nondirective genetic counseling, biases can

sometimes emerge in the choice of words used to

describe conditions, the questions asked, and the

information provided (3,19,55,73).

Finally, as mentioned earlier, public education

appears to resolve some potential stigmatization

associated with carrier screening. Experience with

massive public education efforts for ß-thalassemia,

for example, demonstrates that such outreach can

reduce stigmatization (2,10). On the other hand,

when public education is insufficient (e.g., targeted

only to the screened population and not to all

individuals), stigmatization can be exacerbated, as

witnessed by sickle cell carrier screening (38).

HEALTH CARE COVERAGE

Many view good health care-and access to

it—as a moral right, not a privilege (box 8-B) (46).

Perhaps the most widely raised social question

stemming from the Human Genome Project is what

effect genetic tests have had (and will have) on

health care access in the United States. Because for

most citizens health care access involves private

health insurance, concern focuses on this “market.

Consumers fear exclusion from health care coverage due to genetic or other factors. Such fears are not

unfounded. Health insurance in the United States is

largely employment-based: 147 million Americans

secure health insurance as part of a benefits package

from their or another family member’s employer

(31). A nationwide survey revealed 3 in 10 Americans say they or someone in their household have

stayed in a job they wanted to leave mainly to

preserve health care coverage (17). This so-called

“job lock” freezes an employee with medical

problems (or one with a dependent with medical

problems) in place, because a change in employment

(and health insurance) would likely result in preexisting medical conditions being excluded from

health care coveragetotally or for some period of

time. Job lock also occurs when an individual cannot

secure a new job because of a potential employer’s

fear of increased health care costs. This is particularly true in small businesses, where a single

employee with costly health care needs can result in

cancellation of the company’s policy or premium

increases that become unmanageable for the remaining employees.

A 1989 OTA survey of Fortune 500 companies

and a random sample of 1,000 businesses with at

least 1,000 employees found 11 percent of respondents assess the health insurance risk of job applicants on a routine basis; another 25 percent assess

health risks sometimes. Of these, 9 percent of

employers surveyed also take into account dependents’ potential expenses when considering an individual’s employment application. Forty-two percent

of respondents said the health insurance risk of a job

applicant reduced the likelihood of an otherwise

healthy, able job applicant being hired. Whether the

company was self-funded, used a private carrier, or

some combination of both was not predictive of

response (69). Consternation about restricted health

care for a nongenetic factor has already been voiced

in COUrt (bOX 8-C).
Chapter 8---Discrimination Issues . 193

Box 8-B—Ethics, Genetics, and Health Insurance

As with many issues involving public policy, discussions about the use of genetic information or tests and

health insurance do not center solely on legal considerations. While ethical and legal analyses can share common

ground, the overlap between law and ethics is limited. The law does not reflect a ll moral values held by members

of society, nor can it necessarily be used to resolve ethical dilemmas. Ethical arguments about health care access

and health insurance, for example, often address obligations, rights, or values not explicitly covered by law, and

are used to express incumbency the law does not acknowledge.

In 1983, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and

Behavioral Research concluded that health care is a need, and that:

. . .society has an ethical obligation to ensure equitable access to health care for all. This obligation rests on the

special importance of health care, which derives from its role in relieving suffering, preventing premature death,

restoring functioning, increasing opportunity, providing information about an individual’s condition, and giving

evidence of mutual empathy and compassion (53).

The Commission also pointed out that determining that health care access is a need does not determine the

mechanism for distributing it, only that the system or combination of systems (i.e., public and private) should meet

the need.

In philosophy, justice concerns the distribution of social goods (e.g., health care access) and ills-basically,

that similar cases should be treated alike and unlike cases should be treated differently. If a particular case of just

or unjust treatment arises, the philosophical question becomes, ‘‘What makes these cases like or unlike in a morally

relevant way?’ Failing to state a morally relevant reason for treating the case (or people) differently lays way to

the charge that action is arbitrary, capricious, or unjust.

Human genetics can be viewed as a science of inequality-a study of human particularity and difference.

Genetic factors can be used as answers to the question: What makes these individuals alike or different? For some

cases, the genetic difference provides a morally persuasive answer. Height, for example, is largely determined by

genetics and an important factor in some jobs (e.g., playing professional basketball) but not in other jobs (e.g.,

computer programming). It would not be unjust to use a particular genetic difference-height-in selecting

basketball players, but it would be unjust to use it in hiring computer programmers.

Thus, genetic differences are sometimes good moral reasons for treating different people differently, but in

some cases they are not. Are genetic differences in propensity toward disease, for example, good moral reasons for

treating people differently with respect to their access to health care? To the extent that health insurance is a

mechanism for obtaining access to health care, then arguments about justice and access to health care hold equally

for justice and access to health insurance. If the President’s Commission was correct in concluding that there is a

social obligation to provide equitable access to health care for all, then an obligation exists to ensure that people

who need health care can obtain health insurance, or get access by some other means. If genetic characteristics like

cystic fibrosis make it difficult for people to get the health care they need, then using genetic characteristics to

disqualify individuals for health care coverage would be morally unjust.

SOURCE: Office of Technology Assessment 1992, based on T.H. Murray, “Genetics, Ethics, and Health Insurance,” contract document

prepared for the U.S. Congress, Office of Technology Assessment, July 1991.

Insurers' Attitudes Toward Genetic Risk health care access (49) increase concern about health

Factors: OTA Survey Results insurers’ use of genetic information.

As detailed in chapter 7, organizations offering

Risk classification and the world of insurance health care coverage medically underwrite some

underwriting are arcane to most people. Persons policies-i. e., they classify risks of an individual or

without insurance, especially those who recently goup based on actuarial data. Currently, about 10 to

lost coverage, are puzzled (and, indeed often pan- 15 percent of individuals with health care coverage

icked) by interactions with the insurance industry. are medically underwritten. This selection process—

Any obstacles—real or perceived-encountered as i.e., differentiation based on medical characteristics—

they attempt to obtain individual coverage can lead is an integral part of the insurance mechanism. Risk

to a situation of misunderstanding and mistrust. In classification is the foundation, in fact, for the

many respects, citizens’ generic concerns about concept of private insurance.
194 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 8-C—McGann v. H & H Music Co.

In August 1988, H & H Music Co. in Houston, TX, faced with rising health insurance premiums, decided it

would switch from purchasing coverage from a commercial plan and become self-funded. At the same time, the

company eliminated drug and alcohol treatment benefits and lowered the benefits cap for AIDS to $5,000, compared

to a $1 million cap that was available for other catastrophic problems.

John McGann, who had worked for H & H Music for 5 years, learned he had AIDS in December 1987. In a

suit filed in U.S. District Court, McGann held that the change in coverage was differential treatment aimed at him.

He contended that dropping the coverage was discriminatory because the plan capped the AIDS benefit after he was

stricken and after he informed his employer he had AIDS-the latter claim disputed by H & H Music.

Although Texas insurance law prohibits the denial of health insurance coverage for AIDS and AIDS-related

illnesses, self-funded plans (like that of H & H Music) are exempt from State law because their regulation falls under

Federal jurisdiction defined by the Employee Retirement Income Security Act of 1974 (ERISA; 29 U.S.C. S 1131

et seq.). Thus, McGann could not use State law to support his case. EFUSA does provide that a company cannot

discriminate against people for the purposes of keeping them from attaining their benefits. McGann argued that

H & H Music’s capon AIDS-related benefits violated ERISA because it constituted discrimination motivated by

his prior filing of AIDS-related claims, or was discrumination designed to prevent him from using health benefits

to which he would have been entitled.

The district court ruled against McGann, finding that it was permissible for a self-funded plan to cover any

disease it wanted, and to deny benefits for diseases for which it did not want to offer benefits; McGann died in June

1991. In November 1991, the U.S. Court of Appeals for the 5th Circuit upheld the district court opinion. The

decision has clear implications for cystic fibrosis or other genetic conditions. Under current law, any self-funded

company can cap, modify, or eliminate employees’ health care benefits for a particular condition at any time, as long

as the company complies with the notice requirements in the plan agreement. The Americans With Disabilities Act

of 1990 does not address this issue. In March 1992, the U.S. Supreme Court agreed to hear the case.

SOURCE: Office of Technology Assessment 1992, W on Associated Press, “AIDS Victim’s Case May Define Health Plan Caps on

Expensive Illnesses,” Houston, TX, June 24, 1991; M.A. Bobinski, University of Houston Health Law and Policy Institute, Houston

TX, personal communication August 1991,

Over the last decade, health insurers have exhib- general population, which could spread risk (45). All

ited a tendency to avoid risks, rather than to find

ways to spread risks over a broader base (40). Some

commentators speculate that, overall, genetic analyses will mean fewer people will have access to health

insurance because tests identify or refine risks. They

argue genetic tests will provide the best reason yet

for a nationalized health care system (4,32,65).

Others contend, however, that genetic assays could

detect noncarriers or rule out an individual’s risk for

a disorder and hence increase access to health care

coverage (5 1). That is, making use of genetic

information allows insurers to better assess risks,

such that individuals at elevated risk will pay more

(or be denied access), but people with low risk will

pay less (30). Still others point out that as the number

of genes identified increases, so will the number of

potentially adverse conditions that apply to the

positions depend on the practices and attitudes

insurance carriers actually have toward tests for

genetic disorders, as well as the morbidity and

mortality of a particular condition.

OTA found no data on how third-party payers

view genetic information, generally, and the use of

genetic assays for testing and screening specifically.

To this this void, OTA undertook a survey2 in 1991

to determine how third-party payers might use

genetic information in risk classification, how they

would view presymptomatic, carrier, and prenatal

testing, and what impact insurers project genetic

tests could have on their future practices. This

section uses results from the OTA survey to report

how medical directors at commercial insurance

companies, Blue Cross/Blue Shield (BC/BS) plans,3

z complete ~ta from OTA’S survey of commercial insurers, HMOS, and BCiBS plans are published separately (71).

3 OTA surveyed both chief underwriters and medical directors of BC/BS plans to see whether responses would differ. Eighteen medical directors

responded and 29 chief underwriters responded. To represent a larger pool of plans, only data from the chief underwriters’ survey are used in this chapter

tO describe BC/BS responses. Small sample size and a poor respm.se rate from tie BWS medic~ directors m~es @yZing statistic~ly signific~t

differences in responses between the two BC/BS populations impossible. A separate report addresses this issue and presents relevant medical director

responses (71).
Chapter Discrimination Issues ● 195

Table 8-l—Genetic Information as Medical Information or Preexisting Conditions

Agree Agree Disagree Disagree

Question Respondent strongly somewhat somewhat strongly No responsea

a percentages may not add to 100 due to rounding.

SOURCE: Off Ice of Technology Assessment, 1992,

and health maintenance organizations (HMOs) view

genetic risk factors. As with survey results in chapter

7, these results represent attitudes and practices for

insurers that write individual and medically underwritten group policies only.

The information presented in the following sections should not be construed to represent either

numbers or percentages of commercial entities,

BC/BS plans, or HMOs that have dealt with the

issues presented. Respondents were asked how they

would treat certain conditions or scenarios presented

(currently or in the future, depending on the question), not whether they, in fact, had made such

decisions.

Medical Information Versus Genetic

Information

Do insurers view genetic information as just

another type of medical information? At first glance

it would appear they do. In OTA’s survey, 27

medical directors (53 percent) from commercial

insurers said they ‘‘agree strongly’ or ‘‘agree

somewhat’ with the statement that ‘‘genetic information is no different than other types of medical

information; 22 (43 percent) disagreed to some

extent. For medical directors of HMOs, 13 respondents (57 percent) generally agreed, compared to 8

(35 percent) who generally disagreed. Chief underwriters for BC/BS plans responded similarly: OTA

found 20 respondents (69 percent) who agreed

against 7 (24 percent) who did not. Similarly, OTA

found that, collectively, the majority of respondents

‘‘agree strongly’ or ‘‘somewhat’ that genetic

conditions (e.g., CF or Huntington disease) are

preexisting conditions, but carrier status (e.g., for CF

or Tay-Sachs) is not (table 8-1).4

Yet these general views are not wholly consistent

with what factors insurers view as important to

insurability (not rating). Personal and family medical histories were the most important factors in

determining insurability whether the respondent was

from a commercial insurer, HMO, or BC/BS plan,

and personal history appears to outweigh family

medical history. All 29 commercial vendors (100

percent) offering individual policies in OTA’s survey said personal medical history of significant

conditions was ‘ ‘very important,’ and 36 ( 9 7

percent) who sell medically underwritten group

policies answered similarly. The large majority of

HMOs and BC/BS plans also take personal medical

history into account (table 8-2).

In contrast, OTA found medical directors and

underwriters felt less strongly about “genetic predisposition to significant conditions” as a facet of

insurability than they did about medical history.

Genetic predisposition was a “very important”

criterion to 4 medical directors (14 percent) from

commercial insurers of individual policies, ‘ ‘important’ ‘ to 6 (21 percent), unimportant to 3 (10

percent), and never used by 16 (55 percent). No

commercial-based respondent whose company offers coverage to medically underwritten groups

considered genetic predisposition to significant

conditions an important factor for insurability-18

(49 percent) never used it, 6 (16 percent) considered

4 Throughout this chapter, survey results might not add to 100 percent because of rounding and because ‘no response’ is not includd in the text (but

is included in the tables).
196 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 8-2—Medical History, Genetic Factors, and Insurability

Question: For each category of coverage, please indicate the importance of each of the following factors in determining insurability (not

in rating):

Very Never

Respondent important Important Unimportant used No responsen

individual policies

Medically underwritten groups

a percentages may not add to 100 due to rounding.

SOURCE: Office of Technology Assessment, 1992.

it unimportant, and 12 (32 percent) considered it

important.

With respect to CF carrier screening, OTA found

that “carrier risk for genetic disease’ ‘—where the

individual has no symptoms of the disease—was

‘‘very important” (2 respondents; 7 percent) or

“important’ (5 respondents; 17 percent) in individual policy insurability by commercial insurers. For

medically underwritten groups, carrier risk was

viewed as ‘‘very important’ or ‘‘important” by 1 0

commercial respondents (27 percent). Response for

HMOs and BC/BS plans are also presented in table

8-2.

On the other hand, when specifically asked how

an individual’s application would be treated if the

applicant were asymptomatic but had a family

history of CF, 27 medical directors (93 percent) from

commercial insurers would accept the person with

standard rates; 1 respondent would accept the

applicant at standard rates, but with an exclusion

waiver; and 1 would decline coverage. All 11 HMOs

(100 percent) offering individual coverage would

accept CF carriers at standard rates. But for BC/BS

plans, 16 chief underwriters (55 percent) would

accept at standard rates, while 6 (21 percent) would

accept at the standard rate with a waiting period, and

2(7 percent) would decline to cover the carrier(71 ).5

Thus, the mere fact that a medical director or

underwriter considers carrier status important to

insurability does not appear to translate into difficulties in obtaining health care coverage (rating). For

S lle fact that the underwriters’ responses are used here to repofr BC/BS data vemus tie m~ic~ d~ectors’ responses is not relevant. For the 18

BC/BS medical directors who responded, 9 (50 percent) would accept at standard rates, 3 ( 17 percenl) would accept at standard rates but require a waiting

period, and 2 (11 percent) would decline to cover.
Chapter 8---Discrimination Issues ● 197

those who responded they would accept with a

waiting period or decline to cover, reluctance to

offer standard insurance might stem from not

wanting to pay for possible children or from a

misunderstanding of the meaning of carrier status.

Given these results, do commercial insurers,

HMOs, and BC/BS plans view genetic information

differently than medical information? In response to

the direct question comparing the two, apparently

not. On the other hand, ‘‘genetic predisposition to

significant conditions’ is clearly part of ‘personal/

family medical history of significant conditions. ”

So if genetic information is viewed as a subset of

personal and family medical history, why was it

accorded less weight than medical history in deciding insurability? A few explanations seem plausible.

Medical directors of insurance companies, HMOs,

and BC/BS might have accounted for the probabilistic nature of genetics, and therefore viewed genetics

as ‘ ‘ important,’ ‘ but not “very important. ” They

also might have weighted the importance of genetic

information to determining insurability as less

important than personal and family medical history,

although OTA did not ask them to do so. It also

might be that no single risk---e.g., genetic risk-is as

important as general medical risk and so entire

family history was weighted more heavily. In any

case, OTA’s survey reveals, not surprisingly, that

genetic history is used in assessing risk for individual policies and medically underwritten groups. In

making decisions on insurability and rating based on

genetic history, what seems important is the particular condition and its health care costs-e. g., CF,

diabetes, sickle cell anemia (ch. 7), not that the

consequence is genetically based.

Genetics and Coverage Decisions: One Scenario

Because information derived from CF carrier

screening is primarily useful for reproductive decisionmaking, OTA sought the reactions of commercial insurers, HMOs, and BC/BS plans to a hypothetical situation based on a real-life case (described in

a following section). One alteration from the actual

incident was made in this hypothetical case: Rather

than refusing to pay for all health care of the child,

the scenario was constructed so the insurer refused

to pay for CF-related costs of the child. This change

was made because, as described later, OTA was

aware that insurers in all States and the District of

Columbia must cover (or offer the option to include,

with or without conditions) a newborn child if a

valid insurance contract for the parent exists, and felt

it unethical to ask respondents about breaking the

law, even unknowingly. Specifically, respondents

were asked to indicate whether they ‘agree strongly,’

‘‘agree somewhat, “ “disagree somewhat,’ or ‘disagree strongly,’ with:

Prenatal diagnosis indicates the fetus is affected

with cystic fibrosis; the couple decides to continue

the pregnancy. The health insurance carrier, which

paid for the tests, informs the couple they will have

no financial responsibility for the CF-related costs

for the child.

For commercial vendors, three medical directors

(6 percent) who responded to the OTA question

agreed strongly or somewhat. Thirteen individuals

(25 percent) in this population disagreed somewhat

and 34 (67 percent) disagreed strongly. Among

medical directors at HMOs, 3 respondents (13

percent) agreed to some extent with the decision in

the hypothetical case, but 18 medical directors (78

percent) disagreed, 15 (65 percent) of them strongly.

For chief underwriters of BC/BS plans, 6 respondents agreed (21 percent), either strongly or somewhat, with the decision in the scenario. OTA’s

survey revealed 8 chief underwriters (28 percent)

indicated they disagreed somewhat, and 14 (48

percent) disagreed strongly.

Perspectives on the Future of Genetic Tests

Third-party payors already use genetic information in making decisions about individual policies or

medically underwritten groups. Applicants for such

coverage reveal genetic information when responding to the battery of questions in personal and family

histories. OTA is unaware of any insurer who

underwrites individual or medically underwritten

groups and requires carrier or presymptomatic tests

(e.g., for Huntington or adult polycystic kidney

diseases). Preliminary data from a 1991 Health

Insurance Association of America survey also reveal

no health insurer requires genetic tests in underwriting (56), and ordering tests to review an application

appears remote at this time (l). What will be the

practice in the next 5 or 10 years?

Even a decade from now, OTA’s survey found

that the majority of respondents do not expect to

require genetic tests of applicants who have a family

history of serious genetic conditions, nor do they

anticipate requiring carrier assays (table 8-3). OTA

finds that a minority of commercial insurers who
198 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 8-3—Projected Use of Genetic Tests by Insurers in 5 and 10 Years

Very Somewhat Somewhat Very

Respondent likely likely unlikely unlikely No responsea

How likely do you think it is that your

company/HMO will in the next 5 years:

Require genetic testing for Commercials

applicants with family HMOs

histories of serious BC/BS plans

conditions?

Require carrier tests for Commercials

applicants at risk of HMOs

transmitting serious genetic BC/BS plans

disease to offspring?

Require genetic testing for Commercials

applicants with no known risk HMOs

of genetic disease? BC/BS plans

Offer optional genetic Commercials

testing and carrier HMOs

testing? BC/BS plans

How likely do you think it is that your

company/HMO will in the next 10 years:

Require genetic testing for Commercials

applicants with family HMOs

histories of serious BC/BS plans

conditions?

Require carrier tests for Commercials

applicants at risk of HMOs

transmitting serious genetic BCIBS plans

disease to offspring?

Require genetic testing for Commercials

applicants with no known risk HMOs

Of genetic disease? BC/BS plans

Offer optional genetic Commercials

testing and carrier HMOs

testing? BC/BS plans

a Per@ntages may not add to 100 due to rounding.

SOURCE: Office of Technology Assessment, 1992.

responded believe it will be “very likely” (2

respondents; 4 percent) or “somewhat likely” (17

respondents; 33 percent) that they will, in 10 years,

require genetic testing for applicants who have a

family history of serious conditions. Over the next

decade, no BC/BS chief underwriter considered it

‘‘very likely’ that his or her company would require

genetic testing for applicants who had family

histories of serious disorders; 10 (34percent)replied

they viewed it as ‘‘somewhat likely. ’ Of medical

directors at HMOsS, 3 (13 percent) thought their

HMO would require applicants to have a genetic test

if a family history of a serious disorder existed, and

5 (22 percent) said they considered it “somewhat

likely” tests would be required in this manner—

again, in the next 10 years. A similar distribution of

responses was revealed when respondents were

queried about requiring carrier tests for applicants at

risk of passing on serious genetic conditions to their

offspring (table 8-3). Requiring carrier screening as

a condition of consideration for insurance appears

even more remote than using genetic assays on those

who have family histories of serious disorders (table

8-3).

Few respondents believe their companies will

require genetic tests in either 5 or 10 years, but what

about optional testing? Commercial health insurers

and BC/BS plans do not anticipate that optional

testing or screening will be part of their company’s

policy in 5 or 10 years. It is interesting to note that

a majority of HMO-based medical directors who

responded to OTA’s survey said they considered it

“very likely’ or ‘‘somewhat” likely that their
Chapter 8---Discrimination Issues . 199

Table 8-4—Projected Use of Genetic Information by Insurers in 5 and 10 Years

Very Somewhat Somewhat Very

Respondent likely likely unlikely unlikely No responsea

a permntages may not add to 100 due to rounding.

SOURCE: Office of Technology Assessment, 1992.

HMO would offer optional genetic testing and

carrier testing in 10 years (12 respondents; 52

percent) (table 8-3), The difference in response

between the HMO population versus the commercial

insurers and BC/BS plans could reflect HMOs’

longer history with and emphasis on managed and

preventive care.

Health insurers do not need genetic tests to find

out genetic information. It is less expensive to ask a

question or request medical records. Thus, whether

or not genetic information is available to health

insurers hinges on whether individuals who seek

personal policies, or are part of medically underwritten groups, become aware of their genetic status

because of general family history, because they have

sought a genetic test because of family history, or

because they have been screened in some other

context. Even then, a majority of respondents to

OTA’s survey reported they thought it “somewhat

unlikely’ or “very unlikely” that they would be

using information derived from genetic tests for

underwriting (table 8-4).

Access to Health Insurance After Genetic

Tests: OTA Survey Results

Existing information about how genetic test

results affect individuals’ health care coverage is

largely anecdotal (7). Quantifying such information

has proved difficult, and verifying it, impossible.

Reported insurance rejections on genetic bases

sometimes fail to distinguish among insurance

product lines--+. g., health, life, or disability. Some

cases reflect insurers’ longstanding risk classification practices to decline coverage (or reduce coverage or offer it at increased rates) to individuals in ill

health, regardless of whether it has a genetic basis.

One case from the Baylor College of Medicine,

Houston, TX, however, illustrates why concern is

continually expressed about health-insurer uses of

genetic tests.

A couple in their 30s has a 6-year-old son with CF.

Prenatal diagnostic studies of the current pregnancy

indicate the fetus is affected. The couple decides to

continue the pregnancy. The HMO indicated it

should have no financial responsibility for the

prenatal testing and that the family could be dropped

from coverage if the mother did not terminate the

pregnancy. The HMO felt this to be appropriate since

the parents had requested and utilized prenatal

diagnosis ostensibly to avoid a second affected child.

After a social worker for the family spoke with the

local director of the HMO, the company rapidly

reversed its position (22).

Industry representatives acknowledge that an

individual company could exercise poor judgment,

but contend the problem is not widespread: If the

problem were prevalent, ample court cases could be

cited because patients and their attorneys would not

be passive recipients of ill-based judgments such as

occurred in the case just described (56). Clients and

patient advocates argue to the contrary (6,43) and

maintain that cases like those just mentioned represent the tip of an iceberg.

Do individuals who avail themselves of genetic

tests subsequently have difficulty obtaining or

retaining health insurance? To explore this issue,

OTA decided not to survey either party with a direct

stake in the answer, but chose instead to ask third

parties-genetic counselors and nurses in genetics—

for their firsthand experiences (70), In contrast to the

survey of health insurers, which asked respondents

to speculate about accepting applicants with certain

conditions, this survey attempted to measure actual
200 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

occurrence. Specifically, in June 1991, OTA surveyed 794 members of the National Society of

Genetic Counselors and the International Society of

Nurses in Genetics and asked:

Have any of your patients experienced difficulties

in obtaining or retaining health insurance coverage

as a result of genetic testing? If yes, please provide

details.

Four-fifths (347) of the431 respondents to OTA’s

inquiry currently perform genetic counseling. Fifty

respondents (14 percent) reported they had clients

who had experienced difficulties obtaining or retaining health care coverage as a result of genetic testing

(table 8-5). Because some respondents described

more than one case, the number of affirmative

answers understates the actual number of cases.

Examination of the qualitative responses, some of

which are presented in table 8-6, reveals affirmative

responses represent, at minimum, 68 individual

cases. (Where the term ‘‘patients was used with

specifics not described, a single event was recorded.)

Test results for some conditions where positive

results led to reported difficulties-such as for

Huntington disease, adult polycystic kidney disease,

and Marfan syndrome-were cited by more than one

Table 8-5-Difficulties in Obtaining or Retaining

Health Insurance After Genetic Tests

Question*: Have any of your patients experienced difficulties in

obtaining or retaining health insurance coverage as a result of

genetic testing?

Number Percent

No. . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 81.0

Yes. . . . . . . . . . . . . . . . . . . . . . . . . . . 50 14.4

No answer. . . . . . . . . . . . . . . . . . . . . . 16 4.6

a

1991 OTA survey of genetic counselors and nurses in genetics. Sample

base of 347 represents individuals currently in clinical practice.

SOURCE: Office of Technology Assessment, 1992.

respondent. Since genetic tests for conditions such

as Huntington disease or Marfan syndrome are

available at a limited number of sites, OTA attempted to ascertain whether surveys reporting

patient insurance difficulties were geographically

consistent with known test sites. With few exceptions, the respondent resided in a State where the test

was available. In exceptions, the counselor resided

in a neighboring State.

In addition to affrmative answers, several respondents reported that although they had no direct

experience with a patient’s difficulty in obtaining or

retaining health care coverage, they had clients who

Table 8-6-Case Descriptions of Genetic Testing and Health Insurance Problemsa

Positive test for adult polycystic kidney disease resulted in canceled policy or increased rate for company of newly diagnosed individual.

Positive test for Huntington disease resulted in canceled policy or being denied coverage through a health maintenance organization.

Positive test for neurofibromatosis resulted in canceled policy.

Positive test for Marfan syndrome resulted in canceled policy.

Positive test for Down syndrome resulted in canceled policy or increased rate.

Positive test for alpha-1 -antitrypsin defined as preexisting condition; therapy related to condition not covered.

Positive test for Fabry disease resulted in canceled policy.

Woman with balanced translocation excluded from future maternity coverage.

Positive Fragile X carrier status and subsequent job change resulted in no coverage.

After prenatal diagnosis of hemophilia-affected fetus, coverage denied due to preexisting condition clause.

Denied coverage or encountered difficulty retaining coverage after birth of infant with phenylketonuria.

Woman diagnosed with Turner’s syndrome denied coverage for cardiac status based on karyotype. Normal electrocardiogram failed to

satisfy company.

Family with previous Meckel-Gruberfetus denied coverage in subsequent applications despite using prenatal diagnosis and therapeutic

abortion.

Mother tested positive as carrier for severe hemophilia. Prenatal diagnosis revealed affected boy; not covered as preexisting condition

when pregnancy carried to term.

After a test revealed that a woman was a balanced translocation carrier, she was initially denied coverage under spouse’s Insurance

because of risk of unbalanced conception. Subsequently overturned.

Woman without prior knowledge that she was an obligate carrier for X-linked adrenoleukodystrophy found out she was a carrier. She had

two sons, both of whom were healthy, but each at 50 percent risk. Testing was done so they could be put on an experimental diet

to prevent problems that can arise f rom mid- to late childhood or early adulthood. One boy tested positive. The family’s private pay

policy (Blue Cross/Blue Shield) is attempting to disqualify the family for failing to report the family history under preexisting

renditions.

After birth of child with CF, unable to insure unaffected siblings or themselves.
Chapter 8---Discrimination Issues • 201

feared their coverage would be dropped if they

requested payment for tests from insurers. One

respondent commented that greater than 80 percent

of her clients who have tests for Huntington disease

self-pay. Similarly, others with no direct experience

said they often advise patients not to request

reimbursement for a test so that an insurer would not

learn that testing had occurred. One counselor

offered the information that a patient had refused

testing for adult polycystic kidney disease because

of concern over health insurance. Another respondent reported that a patient with a CF-affected child

had been dropped by one insurance company and

would not consider prenatal testing in the future for

fear her current insurer would not cover the child

should she decide to continue the pregnancy.

Such fears persist despite the fact that most

contracts for individual health insurance coverage

preclude blanket nonrenewal (37,56). Similarly, an

insurer cannot raise rates for an individual who has

been continuously covered if the person develops a

new condition (37). On the other hand, it is legal for

an insurer not to renew a group contract based on the

results of one individual’s genetic or other medical

test. Group policies are rarely guaranteed renewable

(37). In lieu of not offering to renew, an insurer

might opt to levy a steep premium increase at

renewal time.

OTA’s survey reports-conservatively-consumer difficulties in obtaining or retaining health

care coverage after genetic tests. OTA has no basis

for evaluating whether the nonrespondents would be

more or less familiar with patients’ insurance

difficulties and potentially know of additional cases.

The data permit neither extrapolation about the total

number of cases that have occurred in the United

States, nor speculation about any trends.

OTA did not attempt to ascertain whether or not

patients had challenged-or were challenging—

insurers’ rulings. Thus, OTA cannot determine

whether some of the disputes reported in table 8-6

were resolved fully in favor of the consumer because

the initial judgment was deemed improper or illegal.

Some cases, for example, reported a fetus or

newborn had tested positive and coverage had been

denied. In all 50 States and the District of Columbia,

insurers must cover (or offer the option to include)

a newborn child if a valid insurance contract for the

parent exists. However, whether the insurance company can deny certain benefits for the newborn by

evoking the preexisting condition clause generally

contained in all insurance contracts is unclear.

In presenting table 8-6, OTA does not judge the

validity-positively or negatively-of the claim.

Some cases might have been settled in favor of the

individual. Others might have been cases where an

applicant attempted to select against an insurer by

misrepresenting his or her health history, which

would have been resolved against the individual.

In 1991, at least 50 genetic counselors or nurses

in clinical practice knew of at least 68 actual

incidents where their own patients reported difficulties with health insurance due to genetic tests. OTA

estimates, based on the average number of patients

directly counseled, that genetic counselors and

nurses responding to the survey collectively saw

about 110,600 individuals in 1990. However, OTA

did not advise respondents to limit descriptions of

clients’ insurance difficulty to 1990. Thus, it is

unlikely that all reported cases occurred in 1990;

assuming all reported cases occurred in 1990, the 68

cases represent 0.06 percent of patients seen by

survey respondents.

Critics, however, question whether the data—

especially the qualitative descriptions-merely represent more anecdotal stories that unfairly present

one side of the story and for which no response can

be developed (56). Skeptics point out that some of

the cases might fall into the gray area of whether

exclusion or increased rates resulted because an

adverse medical condition was revealed through a

diagnostic test that just happened to be genetic. The

border between what conditions are genetic or not is

blurred, however, and will become increasingly

diffuse. Because genetic-based predictive tests

promise to have a profound impact on clinical

medicine (28)-and because access to medical care

is inextricably linked to private health insurance in

this country-these cases underscore certain policy

dilemmas arising from the increased availability of

genetic assays. For genetic testing or screening to

detect genetic illness (or the potential for illness), the

possibilities for problems are not remote, but real

indeed.

Finally, it is important to note that most of the

cases revealed through the OTA survey do not

involve recessive disorders and carrier screening for

conditions like CF. And while one assumption might

have been that health care coverage for CF carriers

would not be an issue because the individuals are
202 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

asymptomatic, OTA’s survey of health insurers

reveals that a few insurers would require a waiting

period or deny coverage for these individuals.

GENETICS, DISCRIMINATION,

AND U.S. LAW

Federal, State, and local laws provide only

incomplete protection against invidious genetic

discrumination (48). Overall, explicit safeguards

have not been enacted in most jurisdictions to

protect against discrimination, or to allow favoritism, specifically on the basis of genetic characteristics. This section examines how State statutes and

the Americans With Disabilities Act of 1990 (Public

Law 101-336; 42 U.S.C. 12101 et seq.) apply-or

could apply—to discrimination with a genetic basis.

Is genetic dis crirnination a form of racial or

gender discrirnination? Or is it best classified as a

form of disability differentiation? Some argue that

CF carrier screening, specifically, is unlikely to raise

issues under Title VII of the Civil Rights Act (42

U.S.C. 2000e), or its 1991 amendments (Public Law

102-166). That legislation focuses primarily on

protecting groups historically the subject of discrimination. Thus, some argue that only if it can be

shown that CF carrier screening has a disparate

impact on women (67) would the Civil Rights Act

and other protections be pertinent, and that since CF

mutation analysis is done on both men and women,

it does not have such an impact. Others disagree,

asserting that if discriminatory consequences arise

from CF carrier screening, a case could be made that

the Civil Rights Act applies.

State Statutes and Hereditary Conditions

Several States—Arizona, California, Florida, Illinois, Iowa, Kentucky, Louisiana, Maryland, Missouri, New Jersey, New York, Oregon, Virginia, and

Wisconsin-have statutes that specifically mention

testing, counseling, or employment of persons with

hereditary conditions.6 The California (box 8-D),

Maryland, and New Jersey laws recognize that

disease-specific language could prove too rigid and

instead have broad application to “any hereditary

disorder. ” California also draws the distinction

between carriers and those who experience manifestations of the disease. A handful of statutes narrowly

target specific conditions or traits, such as sickle cell

(Florida, Louisiana, New York), hemophilia (Florida, Missouri), CF (Missouri), Tay-Sachs (New

York), or Cooley’s anemia (ß-thalassemia; New

York).

Statutes in at least seven States-Florida, Oregon,

Louisiana, New Jersey, New York, North Carolina,

and Wisconsin-prohibit employment discrimination against persons with any atypical hereditary or

blood trait or with named genetic conditions or

traits. New York law, for example, says that persons

with sickle cell trait and carriers of Tay-Sachs

disease or Cooley’s anemia may not be denied

opportunities for employment unless their disorder

would prevent them from performing the job. Some

State statutes address issues beyond employment

discrimination. Wisconsin and Arizona, for example, prohibit certain forms of insurance discrimina

tion. Genetic-related State laws also prohibit certain

types of screening (Florida), provide funding for

research or treatment (Florida, Iowa), or require

information on or testing of genetic disorders be

given to marriage applicants (California, Illinois,

Kentucky, New Jersey, Virginia). Other State laws

are concerned with genetic counseling and confidentiality (Missouri).

The Americans With Disabilities Act of 1990

In 1990, Congress enacted the ADA, a comprehensive civil rights bill to prohibit discrimination on

the basis of disability.7 Unlike the Rehabilitation Act

of 1973, which is still in force, the ADA extends

antidiserimin ation protection of persons with disabilities to private sector employment, public services, public accommodations, and telecommunications.

State and local antidiscrirnination legislation supplement Federal law and are not preempted by the

ADA. All 50 States have disability statutes, 48 of

b Arizona Rev, Sht. Sec. 20-44$s (1991); California Healti and Safety Code, Sec. 150, 151, 155,309,341 (West 1990); ~Ori@ Statute, Sm. 385.206

(1989); Illinois 1990 Public Act 86-1028; Iowa Code Sec. 136A.2 (1989); Kentucky Rev. Stat. Ann. Sec. 402.320 (Ban&Baldwin 1991); Imuisiana

Rev. Stat. Ann. Sec. 46.2254 (West 1982); Maryland Health-Gen. Code Ann. Sec. 13-101; Missouri Rev. Stat. Sec. 191 (1989); New Jersey Rev. Stat.

Sec. 26:5 B-3 (1987); New York Laws 900 (1990); Virginia Code Ann. Sec. 32.1-68. (1990); 1991 Wise. Act 177 (signed Mar, 5, 1992).

T Two Federal disability laws other than the ADA have potential application to broad considerations of genetic discrimination but are not discussed

in this report-the Education for All Handicapped Children Act of 1975 (Public Law 94-142, 89 Stat. 773; renamed the Individuals With Disabilities

Education Act of 1990, Public Law 101-476, 104 Stat. 1142) giving all school-aged children with disabilities the right to a free public education in the

least restrictive environment appropriate to their needs and the Fair Housing Amendments Ad of 1988 (Public Law 1OO-43Q 102 Stat. 1619).
Chapter 8---Discrimination Issues . 203

Box 8-D—The California Hereditary Disorders Act of 1990

California law is the most comprehensive of State statutes specifically addressing discrimination and

hereditary conditions. It touches on access to health care services, professional and public education about genetic

disorders, confidentiality of genetic information, voluntariness of genetic screening, and continued reproductive

freedom for those at risk of passing on a disabling genetic trait. The 1990 Hereditary Disorders Act finds that “In

order to minimize the possibility for the reoccurrence of abuse of genetic intervention in hereditary disorders

programs . . . [t]he Legislature finds it necessary to establish a uniform statewide policy for screening for hereditary

disorders.

The statute mandates that:

. The public . . . should be consulted before any rules, regulations, and standards are adopted by the State

Department of Health Sexvices.

. Clinical testing procedures established for use in programs, facilities, and projects be accurate and provide

maximum information, and that the testing procedures produce results that are subject to minimum

misinterpretation.

. No test(s) shall be performed on any minor over the objection of the minor’s parents or guardian, nor may

any tests be performed unless such parent or guardian is fully informed of the purposes of testing and is given

reasonable opportunity to object to such testing.

. No testing, except initial screening for phenylketonuria and other diseases that maybe added to the newborn

screening program, shall require mandatory participation. No testing programs shall require restriction of

childbearing, and participation in a testing program shall not be a prerequisite to eligibility for, or receipt

of, any other service or assistance from, or to participate in, any other program, except where necessary to

determine eligibility for further programs of diagnoses of or therapy for hereditary conditions.

. Counseling services for hereditary disorders shall be available through the program or a referral source for

all persons determined to be or who believe themselves to be at risk for a hereditary disorder as a result of

screening programs. Such counseling shall be nondirective, emphasize informing the client, and not require

restriction of childbearing.

. All participants in programs on hereditary disorders shall be protected from undue physical and mental harm,

Those determined to be affected shall be informed of the nature, and where possible, the cost of available

therapies or maintenance programs, and be informed of the possible benefits and risks associated with such

therapies and programs.

. All testing results and personal information generated from hereditary disorders programs shall be made

available to an individual over 18 years of age, or to the individual’s parent or guardian.

. All testing results and personal information from hereditary disorders programs obtained from any

individual, or from specimens from any individual, shall be held confidential. An individual whose

confidentiality has been breached may recover compensatory damages. In addition, he or she may recover

civil damages not to exceed $10,000, reasonable attorney’s fees, and the costs of litigation.

California’s law, any violation of which is a misdemeanor, authorizes the State Department of Health Services

to administer a statewide prenatal screening program for genetic disorders. The Department shall also develop an

education program designed to educate physicians and the public concerning the uses of prenatal testing, as well

as to set quality control standards for clinics offering prenatal screening. Funding is to be assured for screening

services for low income women. To emphasize the noneugenic purposes of the program, special attention is paid

to voluntary participation. In addition, repeated mention is made that screening and counseling should emphasize

information delivery, and should not be directed toward persuading or coercing individuals to forego childbearing

or conception.

Although Maryland has a law with similar goals, the California legislation has not been widely adopted, nor

have its broad goals been fully realized due to funding constraints. It could serve as a model for State efforts to ensure

that genetic tests take their place beside other, voluntary health services, while simultaneously discouraging third

parties from discriminating against those who suffer from or carry traits for genetic disorders. Conversely, it can

also be viewed as a poor model that represents unnecessary government intervention and control of medical and

laboratory genetics.

SOURCE: Office of Technology Assessment, 1992, based on California Health and Safety Code, Sec. 150, 151, 155,309,341 (West 1990); 1990

California Senate Bill 1008 (ch. 26).
204 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

them prohibiting discrimination in the private, as

well as public, sector; Alabama’s and Mississippi’s

laws extend to the public sector only (58). State and

local disability laws are enforced by human rights

organizations that are often successful at both public

education and at alternative dispute resolution,

resulting in settlement of over four-fifths of their

cases (27). Thus, such laws might remain important

protections against genetically based discrimination, although only a few State cases directly involve

genetic discrimination (58).

The following sections examine how genetic

illness, predisposition to genetic conditions, or

carrier status appear to be treated under provisions of

the ADA and Equal Employment Opportunity

Commission (EEOC) regulations that define disability and impairment.

PUBLIC LAW 101-

The Americans With Disabilities Act (Public Law 101 -336).

What Is Disability?

Disability is defined broadly in the ADA to mean:

(A) a physical or mental impairment that substantially limits one or more of the major life activities. . . . (B) a record of such impairment, or (C)

being regarded as having such an impairment (42

U. S.C.A. Sec. 12102(2)).

This definition is based on the term “handicap” in

the Rehabilitation Act of 1973 (29 U.S.C. Sec.

706(7)(B) (1988)) and Fair Housing Amendments

Act of 1988 (45 U.S.C. Sec. 3602(h) (Supp. 1990)).

Congress intended that regulations implementing

the Rehabilitation Act and the Fair Housing Amendments Act apply in interpreting the term ‘ ‘disability” in the ADA (21).

In spelling out the meaning of subsection (A), the

Senate Report states:

“Physical or mental impairment” includes the

following: any physiological disorder or condition,

disfigurement, or anatomical loss affecting any of

the major bodily systems, or any mental or psychological disorder such as mental retardation, mental

illness or dementia. . . . The term physical or mental

impairment does not include simple physical characteristics, such as blue eyes or black hair. . . [nor does

it include] environmental, cultural, and economic

disadvantages [in and of themselves] (72).

A person with a disability includes someone who

has a “record” of or is ‘‘regarded’ as having a

disability, even if there is no actual incapacity.

Further, a “record” of disability means that the

person has a history of impairment, or has been

misclassified as having an impairment (72). This

provision protects those who have recovered from a

disability that previously impaired their life activities. In this manner, Congress recognized that people

who have recovered from diseases such as cancer—

or have diseases under control such as diabetes---can

face discrimination based on misunderstanding,

prejudice, or irrational fear (21,42,50), and so still

merit protection.

Additionally, individuals regarded as having disabilities include those who have an impairment, but

do not have limitations in their major life functions

and yet are treated as if they did have such

limitations. Thus, the ADA encompasses people

who are discriminated against based on a false belief

that they have disabilities (61). This provision is

particularly important for individuals who are per-
Chapter 8-Discrimination Issues ● 205

Figure 8-l-Genetics and the Americans With Disabilities Act of 1990

_ Significant impairment ~ Covere d

CONDITIONS

PREDISPOSITIONS —--+>

CARRIERS ~ Asymptomatic ~ Likely not covere d

SOURCE: Office of Technology Assessment, 1992.

ceived to have stigmatic conditions. That is, society’s reaction, rather than the disability itself,

deprives the person of equal enjoyment of rights and

services (27).

The ADA and Genetics

Given the dearth of State legislation specific to

genetic characteristics, if the ADA addressed this

issue it would create a nationwide standard of

protection. The ADA is silent with respect to

genetics, per se, however, as are the EEOC’s

regulations implementing it (29 CFR part 1630; 56

FR 35726) (58,59). Furthermore, the legislative

history of the ADA indicates that little attention was

given to the role of genetics in discrimination.

During debate on the ADA, the Congressional

Biomedical Ethics Advisory Committee was informed that genetic discrumination was “not raised

or discussed, ’ and so could not be addressed by the

conference committee-although several Representatives supported the argument that the ADA will

also benefit individuals who are identtiled through

genetic tests as being carriers of a disease-associated

gene (27). The following sections examine the

apparent coverage--or lack of coverage—for different genetic statuses under the ADA (figure 8-l).

Genetic Conditions. Disability under the ADA is

defined only according to the degree of impairment,

with no distinction between disabilities with genetic

origins and those without. Congress and the courts

have long recognized disabilities of primarily or

partial genetic origin, including Down syndrome,

CF, muscular dystrophy, multiple sclerosis, heart

disease, schizophrenia, epilepsy, diabetes, and arthritis (8,24,34,72). In fact, the legislative history of

the ADA cites muscular dystrophy as an example of

a condition covered by the ADA.

That the condition is genetic, then, is not the

defining event. At issue is how severely the disability interferes with life activities, not its origins. In

defining disability, the courts require a ‘ ‘substantial” limitation of one or more major life activities.

A genetic condition that does not cause substantial

impairment might not constitute a disability, unless

others treat the person as disabled. Thus, significant

cosmetic disfigurements from burns or neurofibromatosis could be classified as disabilities if public

prejudices act to limit the life opportunities of those

with the cosmetic problem (72).

Genetic Predisposition. The ADA expressly protects not only individuals who actually have disabilities, but also those who are ‘‘regarded’ or perceived as having them. It judges disability not by an

objective measure of inability to perform tasks, but

also subjectively by the degree to which the public

makes the condition disabling through misunderstanding or prejudice (21,50). This definition might

then apply to individuals who are asymptomatic but

predicted to develop disease in the future-i.e.,

persons who are sometimes referred to as the

“healthy ill” or “at risk” (16,27).

One commentator argues that the ADA’s legislative history indicates that genetic predisposition

might be encompassed (27). For example, one

Congressman stated during the 1990 debate over the

conference report that persons who are theoretically

at risk ‘‘may not be discriminated against simply

because they may not be qualified for a job

sometime in the future. Several Representatives

agreed, arguing that those at risk for future disabilities are to be ‘‘regarded” as having disabilities (136

Congressional Record H4614, H4623, H4624,

H4626). On the other hand, no further substantive

discussion on the issue occurred (58), and as
206 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

described later, the EEOC rejects the premise that

genetic predisposition is covered.

Carrier Status. The ADA’s prohibition of discrimination and case law generally hold that employment decisions must be based on reasonable

medical judgments showing that the disability

prevents the individual from meeting legitimate

performance criteria (9,26,61,66). For asymptomatic carriers of recessive genetic conditions such as

CF, sickle cell anemia, the thalassemias, and TaySachs, there is no disability per se. Carriers appear

not to be covered by the ADA. Such individuals are,

however, at risk of having an affected child if their

partners also carry the trait, and are often themselves

misunderstood to be affected by the disease. Discrimination against asymptomatic carriers, therefore, arguably can constitute discrimination based

on a perception of disability.

The Equal Employment Opportunity

Commission Regulations

Although the ADA does not provide explicit

guidance about how genetic information should be

viewed, the lack of this type of specificity in the

literal reading of a law is not unusual. Instead, the

executive branch (the EEOC in this case), relying on

the bill’s legislative history and congressional intent, interprets the legislation and issues regulations

for executing the law. Thus, speculation about any

perceived vagueness of the law could be addressed

through public comment on EEOC’s proposed rules.

In February 1991, EEOC proposed regulations for

implementing the ADA (56 FR 8578). EEOC’s

proposed regulations did not specifically prohibit

discrimination against carriers or persons who are

identified presymptomatically for a late-onset genetic condition (e.g., adult polycystic kidney disease

or Huntington disease). This perceived void led the

Joint Working Group on Ethical, Legal, and Social

Issues (ELSI) of the NIH and Department of Energy

(DOE) to urge that the EEOC revise its proposed rule

to explicitly include such individuals (74). Similarly, the members of the NIH/DOE Joint Subcommittee on the Human Genome endorsed the ELSI

Working Group’s action, and recommended that

EEOC make explicit the protection of carriers or

those diagnosed presymptomatically (i.e., that no

individual shall be discriminated against on the basis

of genetic makeup) (5).

In July 1991, EEOC published the final rule

addressing the definitions of disability and impairment under the ADA (56 FR 35726). The final rules

did not reflect the suggestions of either the ELSI

Working Group or the Joint Subcommittee on the

Human Genome. In fact, EEOC specifically amended

its interpretive guidance “to note that the definition

of the term ‘impairment’ does not include characteristic predisposition to illness or disease’ (56 FR

35727).

Additionally, in correspondence to the Joint

Subcommittee on the Human Genome, EEOC stated

that ‘‘the ADA does not protect individuals, who are

not otherwise impaired, from discrimination based

on genotype alone’ (20). Thus, from EEOC’s

perspective, asymptomatic carriers are not encompassed by the ADA’s provisions. With respect to

individuals diagnosed presymptomatically, EEOC

has concluded that “such individuals are protected,

either when they develop a genetic disease that

substantially limits one or more of their major life

activities, or when an employer regards them as

having a genetic disease that substantially limits one

or more of their major life activities’ (20). Again, as

with carriers, EEOC’s interpretation is that individuals who are identified as at risk for a late-onset adult

disorder are not protected by the ADA until the

condition is manifest. Some argue that the ADA

might need amending if carriers or presymptomatic

individuals come to be widely perceived as having

a disability, thus invoking the law’s broader definition.

The ADA and Health Insurance

An employer’s fear of future disability in an

applicant’s family that would affect the individual’s

usage of health insurance and leave time would also

appear to be a prohibited basis for discrimination

under the ADA. Nevertheless, the ADA does not

speak to this point directly, and so leaves open for

future interpretation whether employers may discriminate against carriers who are perceived as more

likely to incur extra costs due to illnesses likely to

occur in their future children. The ADA specifically

states that it does not restrict insurers, health care

providers, or other benefit plan administrators horn

carrying out existing underwriting practices based

on risk classification (27,59). Nor does the ADA

make it clear whether such employers may question

individuals about their marital or reproductive plans

prior to offering employment or enrollment in an
Chapter Discrimination Issues ● 207

insurance plan, (As discussed earlier and described

in box 8-C, however, after a person is hired,

self-funded insurance plans can alter benefits to

exclude or limit coverage for specific conditions. )

SUMMARY AND CONCLUSIONS

Among the many issues raised by prospects of

both routine carrier screening for CF and increased

availability of DNA-based diagnostic or predictive

tests are stigmatization and discrimination. For CF

carrier screening, stigmatization might focus on the

notion that it is irresponsible for people who are at

risk of having offspring who might have a genetic

condition to have affected children, With respect to

discrimination, CF carrier screening raises questions

about access to health care coverage and Federal

discrimination law.

Few empirical studies have examined stigmatization of CF carriers directly, but several projects are

underway. Existing research on stigmatization and

carriers for Tay-Sachs or sickle cell anemia have a

bearing on carrier screening for CF, but only in a

limited manner. These studies can guide efforts to

help clients avoid feelings of guilt or shame that

could be associated with being identified as a CF

carrier, but provide less concrete approaches that

must be taken to educate the public. Historical

perspectives can assist health care professionals in

counseling clients identified as carriers, but the

greatest barrier-public perception of genetic status—

will require new initiatives in large numbers. Public

education for Tay-Sachs carrier screening worked

because the target population was both defined and

inclined to seek screening. In contrast, the potential

target population for CF carrier screening is larger

and more diffuse, with unknown attitudes toward

carrier identification.

With respect to accessing health care coverage

and CF carrier screening, OTA’s survey found that

the majority of third-party payers offering mdividual

or medically underwritten group policies view

genetic information as no different from other types

of medical information. Genetic information is used

in decisions determining risk classification and

underwriting, but no blanket statement can be made

as to the weight placed on it. Not surprisingly,

respondents rank genetic information as relatively

more important to individual policies than for

medically underwritten groups. Medical directors

and chief underwriters view personal and family

medical histories as the most important determinants

in classfying and rating candidates for individual or

medically underwritten insurance. Whether a condition is genetically based or not is of less import. The

increased availability of genetic information, however, adds to the amount of medical information that

insurers can use for underwriting. Concern is expressed this additional information will lead to risk

assessments that are so accurate on an individual

level that they undermine the risk spreading function

of insurance.

OTA’s survey of health insurers illustrates why

some claims of inappropriate or illegal health care

coverage decisions based on genetic test results have

occurred. These decisions might continue to arise, or

they could disappear with time if such insurers

become familiar with and educated about the significance of CF carrier screening. OTA’s survey of

genetic counselors and nurses reveals more than 14

percent of respondents have clients who reported

difficulties in obtaining or retaining health insurance

due to results from genetic tests.

Finally, Federal antidiscrimination law, particularly the Americans With Disabilities Act, clearly

encompasses individuals who have a genetic condition that substantially limits one or more major life

activities. According to regulations promulgated by

the Equal Employment Opportunity Commission,

however, ADA does not include predisposition to

illness or disease if the individual is asymptomatic.

Similarly, carriers of genetic disorders per se are not

covered by ADA’s provisions according to EEOC;

genetic status is not a defining factor in determining

disability or impairment under the ADA. Nor does

the ADA restrict insurers from carrying out existing

underwriting practices based on risk classification.

Thus, if any health care reform is viewed as

necessary because of the future of widespread carrier

screening for CF, predictive testing for other disorders, or increased knowledge stemmin g from the

Human Genome Project, it will necessarily, and

probably appropriately, be done under the umbrella

of general health care reform currently being debated in the United States.

CHAPTER 8 REFERENCES

1. American Council of Life Insurance and Health

Insurance Association of America, Report of fhe

ACLI-HIAA Task Force on Genetic Testing, 1991

(Washington, DC: American Council of Life Insur-
208 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

2.

3

4.

5.

6.

7,

8.

9.

10.

11.

12.

13.

14.

15.

ance or Health Insurance Association of America,

1992).

Angastiniotis, M, Cyprus Thalassaemia Centre, Archbishop Makarios III Hospital, Nicosi% Cyprus,

“Development of Genetics Se~ices From Disease

Oriented National Genetics Programs,’ presentation

at the 8th International Congress of Human Genetics,

Washington, DC, October 1991.

Asch, A., ‘Ethical hnplications of Population Screening for Cystic Fibrosis: Disability and Stigmatization, ” contract document prepared for the U.S.

Congress, Office of Technology Assessment, May

1991.

Beckwith, J., Harvard University, in N. Touchette,

“Genes In Good Hands With Insurers?,’ JournaZ of

NIH Research 2:37, 1990.

Berg, P., and Wolff, S.$ National Institutes of

Health/Department of Energy Joint Subcommittee on

the Human Genome, letter to Eva J. Kemp, Chairman, Equal Employment Opportunity Commission,

July 10, 1991.

Billings, P. R., “Genetics and Insurance Discrimination,” presentation before the U.S. Congress, Office

of Technology Assessment advisory panel on Genetic Monitoring and Screening in the Workplace,

March 1989.

Billings, P. R., Kohn, M. A., de Cuevas, M., et al.,

“Discrimination as a Consequence of Genetic Testing,” American Journal of Human Genetics 50:476-

482, 1992.

Bowen v. American Hospital Association, 476 U.S.

610 (1986).

Burris, S., “Rationality Review and the Politics of

Public Health,” Villanova Law Review 34:933-993,

1989.

Cao, A., Istituto di Clinica e Biologia dell’Etil

Evolutiva, University Studi, Calgliari, Italy, “A

Disease Oriented National Health Service,’ presentation at the 8th International Congress of Human

Genetics, Washington, DC, October 1991.

Childs, B., “The Personal Impact of Tay-Sachs

Carrier Screening,” Tq-Sachs Disease: Screening

and Prevention, M.M. Kaback (MI.) (New YorL NY:

Alan R. Liss, Inc., 1977).

Childs, B., Gordis, L., Kaback, M. M., et al., “TaySachs Screening: Social and Psychological Impact,”

American Journal of Human Genetics 28z550-558,

1976.

Clarke, A., “Is Non-Directive Genetic Counseling

Possible?,” Lxzncet 338:998-1991.

Clew, C.L., and Scriver, C.R., “Knowledge and

Attitudes Toward Genetic Screening Among HighSchool Students: The Tay-Sachs Experience,” Pediatrics 59:86-91, 1977.

Clew, C.L., and Scriver, C.R., “The Adolescent

Copes With Genetic Screening: A Study of Tay16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

Sachs Screening Among High-School Students,”

Tq-Sachs Disease: Screening and Prevention, M.M.

Kaback (cd.) (New York NY: Alan R. Liss, Inc.,

1977).

Council for Responsible Genetics, Human Genetics

Committee, “Position Paper on Genetic Discrimination,” Genewatch, May 1990, p. 3.

Eckholrn, E., “Health Benefits Found to Deter Job

Switching,” New York Times, Sept. 26,1991, p. Al.

Eddy, D.M., “HOW To Think About Screening,”

Common Screening Tests, D.M. Eddy (cd.) (Philadelphia, PA: American College of Physicians, 1991).

Elias, S., and Annas, G.J. (eds.), Reproductive

Genetics and the Law (Chicago, IL: Year Book

1987).

Equal Employment Opportunity Commission, Washington, DC, letter to P. Berg and S. Wolff, Aug. 2,

1991.

Feldblurn, C.R., “The Americans With Disabilities

Act Definition of Disability,” The Labor Lawyer

7:11-26, 1991.

Fembach, S. D., Baylor College of Medicine, Houston, TX, personal communication, November 1991.

Fletcher, J. F., “Knowledge, Risk and the Right to

Reproduce: A Limiting Principle,’ Genetics and the

Law H, A. Miluns& and G.J. Annas (eds.) (New

York, NY: Plenum, 1980).

Gerben v. Holsclaw, 692 F. Supp. 557 (E.D. Pa.

1988).

Goffman, E., Stigma: Notes on the Management of

Spoiled Identity (Englewood Cliffs, NJ: PrenticeHall, 1963).

Gostin, L., “The Future of Public Health Law,”

American Journal of Luw and Medicine 12:461490,

1986.

Gostin, L., “Genetic Discrimination: The Use of

Genetically Based Diagnostic and Prognostic ‘Ilxts

by Employers and Insurers,” American Journal of

Law andllledicine 17(l&2):109-144, 1991.

Green, E.D., and Waterston, R.H., “The Human

Genome Project: Prospects and Implications for

Clinical Medicine,” Journal of the American Medical Association 266:1966-1975, 1991.

Hahn, H., “The Politics of Physical Differences:

Disability and Discrimination,” JournaZ of SociaZ

Issues 44:39-47, 1988.

Havighurst, C. C., Duke University School of Law,

Durham, NC, personal communication, September

1991.

Health Insurance Association of America, Source

Book of Health Insurance Data, 1989 (Washington,

DC: Health Insurance Association of America, 1989).

Holtzman, N. A., Johns Hopkins University, in N.

Touchette, “Genes In Good Hands With Insurers?,”

Journal of NIHResearch 2:37, 1990.
Chapter 8-Discrimination Issues ● 209

33,

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

Holtzman, N. A., and Rothstein, M. A., “Invited

Editorial: Eugenics and Genetic Discrimination,”

American Journal of Human Genetics 50:457459,

1992.

Jane Doe v. Region 13 Mental Health-Mental

Retardation Commission, 704 F.2d 1402 (5th Cir.

1983).

Kabac~ M. M., Becker, M., and Ruth, V. M., “Sociologic Studies in Human Genetics: 1, Compliance

Factors in a Voluntary Heterozygote Screening

Program,” Ethical, Social and legal Dimensions of

Screening for Human Genetic Disease, D. 13ergsma

(cd.) (New York, NY: Stratton Intercontinental

Medical Book Corp., 1974).

Kaplan, F., Clew, C., and Scriver, C. R., “Cystic

Fibrosis Carrier Screening by DNA Analysis: A Pilot

Study of Attitudes Among Participants,” American

Journal of Human Genetics 49:240-243, 1991.

Kass, N. E., Johns Hopkins University, personal

communication, December 1991.

Kenen, R. H., and Schmidt, R. M., ‘‘Stigmatization of

Carrier Status: Social Implications of Heterozygote

Genetic Screening Programs,’ American Journal of

Public Health 68:116-1120, 1978,

Kimura, R., “Genetic Screening and Testing: Report

of a Working Group,’ Genetics, Ethics, and Human

Values: Hurnun Genome Mapping, Genetic Screening, and Gene Therapy-Proceedings of the XXIVth

CIOMS Round Table Conference, Z. Bankowski and

A.M. Capron (eds,) (Geneva, Switzerland: Council

for International Organizations of Medical Sciences,

1991).

Kosterlitz, J., “Unrisky Business, ” National Journal, Apr. 6, 1991, pp. 794-797.

Lippman, A., “Prenatal Genetic Testing and Screening: Constructing Needs and Reinforcing Inequities, ” American Journal of Law and Medicine

17(l&2):15-50, 1991.

Mayerson, A., “The Americans With Disabilities

Act-An Historic Overview, ” The Lubor L.uwyer

7:1-9, 1991.

Meyers, A. S., National Organization for Rare Disorders, “The Rising Cost of Health Insurance,”

testimony, U.S. House of Representatives, Committee on Energy and Commerce, Subcommittee on

Commerce, Consumer Protection, and Competitiveness, Apr. 30, 1991.

Myers, S. T., and Grasmick, H. G., ‘The Social Rights

and Responsibilities of Pregnant Women: An Application of Parson’s Sick Role Model,’ The Journal of

Applied Behavioral Science 26:157-172, 1990.

Murray, R. F,, Jr., Howard University College of

Medicine, Washington, DC, personal communication, March 1992.

Murray, T. H., “Genetics, Ethics, and Health Insurance, ’ contract document prepared for the U.S.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

Congress, Office of Technology Assessment, July

1991.

National Center for Human Genome Research, National Institutes of Health, ‘Ethical, Legal and Social

Issues Program, National Center for Human Genome

Research: Grant-Making Status Report,” August

1991.

Natowicz, M. R., A.@, J. K., and Alper, J. S., “Genetic Discrimination and the Law, ’ American Journal of Human Genetics 50:465-475, 1992.

Northwestern National Life Insurance Co., “Americans Speak Out on Health Care Rationing” (Minneapolis, MN: Northwestern Life Insurance Co., 1990).

Parmet, W., “Discrimin ation and Disability: The

Challenges of the ADA, ’ L.uw, Medicine, andHealth

Care 18:331-344, 1990.

Pauly, M.V., bonard Davis Institute of Health

Economics, University of Pennsylvania, Philadelphia, PA, personal communication, September 1991.

Peterson, K. S., ‘‘Pregnancy Often Seen As Illness,”

USA Thy, Mar. 12, 1992.

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Securing Access to Health Care

(Washington, DC: U.S. Government Printing Office,

1983).

Purdy, L. M., “Genetic Diseases: Can Having Children Be Immoral?,” Ethical Issues in Modern

Medicine, 3rd cd., J.D. Arras and N.K. Rhoden (eds.)

(Mountain View, CA: Mayfield, 1989).

Rapp, R., ‘‘Chromosomes and Communication: The

Discourse of Genetic Counseling,’ Medical Anthropology Quarterly 2:143-157, 1988.

Raymond, H. E., Health Insurance Association of

America, Washington, DC, personal communication,

December 1991.

Richardson, S. A., “Attitudes and Behavior Toward

the Physically Handicapped,” Birth Defects: Original Article Series 12:15-34, 1976.

Rothstein, M. A., University of Houston Health Law

and Policy Institute, Houston, TX, remarks at U.S.

Congress, Office of Technology Assessment workshop, “Cystic Fibrosis, Genetic Testing, and SelfInsurance Under ERISA,” Aug. 6, 1991.

Rothstein, M. A., “Genetic Discrimin ation in Employment and the Americans With Disabilities Act,’

Houston Luw Review, vol. 29, in press, 1992.

Schneider, J., and Conrad, P., Having Epilepsy: The

Experience and Control of Illness (Philadelphia, PA:

Temple University Press, 1983).

School Board of Nassau County, Florida v. Arline,

480 U.S. 273 (1987).

Schulman, J. D., Genetics & IVF Institute, Fairfax,

VA, personal communication, December 1991.

Seligmann, J., “Whose Baby Is It, Anyway ?,”

Newsweek, Oct. 28, 1991.
210 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

64.

65.

66.

67.

68.

69.

70.

Singer, E., “Public Attitudes Toward Genetic Testing, ’ ‘ Population Research and Policy Review,

10:235-255, 1991.

Stone, D., Brandeis University, in S. Brownlee and J.

Silbemer, ‘‘The Assurances of Genes,” U.S. News&

World Report, July 23, 1990.

Susser, P., “The ADA: Dramatically Expanded

Federal Rights for Disabled Americans,” Employee

Relations Law Journal 16(2):157-176, 1990.

United Auto Workers v. Johnson Controls, Inc., 111

S. Ct. 1196 (1991).

U.S. Congress, Office of T=hnology Assessment,

Genetic Monitoring and Screening in the Workplace,

OTA-BA-455 (Washington, DC: U.S. Government

Printing Office, October 1990).

U.S. Congress, Office of Technology Assessment,

Medical Monitoring and Screening in the

Workplace: Results of a Survey-3a ckground Paper,

OTA-BP-BA-67 (Washington, DC: U.S. Government Printing Office, October 1991).

U.S. Congress, Office of Technology Assessment,

Cystic Fibrosis and DNA Tests: Policies, Practices,

and Attitudes of Genetic CounselorsAesults of a

710

72.

73,

74.

Survey, OTA-BP-BA-97 (Washington, DC: U.S.

Government Printing Office, forthcoming 1992).

U.S. Congress, Office of Twhnology Assessment,

Cystic Fibrosis and Genetic Screening; Policies,

Practices, and Attitudes of Health Insurers-Results

of a Survey, OTA-BP-BA-98 (Washington, DC: U.S.

Government Printing Office, forthcoming 1992).

U.S. Congress, Senate, Committee on Labor and

Human Resources, Americans With Disabilities Act

of 1990, report to accompany S. 933, S. Rpt. 101-116

(Washington, DC: U.S. Government Printing Office,

1989).

Wertz, D. C., and Fletcher, J. C., “An International

Survey of Attitudes of Medical Geneticists Toward

Mass Screening and Access to Results,” Public

Health Reports 104:35-44, 1989.

Wexler, N. S., Beckwith, J., Cook-Deegan, R. M., et

al., “Statement of Recommendations by the Joint

Working Group on Ethical, Legal, and Social Issues

(ELSI) Concerning Genetic Discrimination and ADA

Implementation, Apr. 29, 1991,” Human Genome

News, September 1991.
Chapter 9

Costs and Cost-Effectiveness
Contents

Page

A CAUTIONARY NOTE . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

COSTS OF CYSTIC FIBROSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .214

Medical Direct Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .214

Nonmedical Direct Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

COSTS OF CARRIER SCREENING FOR CYSTIC FIBROSIS . . . . . . . . . . . . . . . . . . . . . 216

KEY VARIABLES AND ASSUMPTIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Test Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Participation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Reproductive Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

Screening Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

COSTS AND SAVINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Costs With No Carrier Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .220

Calculating Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

Calculating Cost Offsets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

Alternative Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .222

QUALIFICATIONS ON THE ANALYSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

CHAPTER 9 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

Box

9-A. Licensing of Polymerase Chain Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Tables

9-1. Estimated Average Annual Medical Expenses for Cystic Fibrosis Treatment . . . . . 215

9-2. Annual Cost of Medical Care for Cystic Fibrosis Patients . . . . . . . . . . . . . . . . . . . . . . 215

9-3. Costs for Cystic Fibrosis Carrier Tests at Selected Facilities . . . . . . . . . . . . . . . . . . . . 216

9-4. Costs, Cost Offsets, and Net Savings for Base Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

9-5. Effect of Assumptions on Net Savings Over No Screening . . . . . . . . . . . . . . . . . . . . . . 223
Chapter 9

Costs and Cost-Effectiveness

One of the least examined of the many issues

surrounding carrier screening for cystic fibrosis (CF)

is that of costs and cost-effectiveness. OTA found no

comprehensive studies on the cost-benefit and

cost-effectiveness of screening large numbers of

people for CF carrier status, although one recent

study examined the net economic benefit of prenatal

screening for CF (1 1).

How much money might be involved in largescale CF carrier screening? Under which, if any,

conditions would it be cost-effective? What factors

are important in optimizing cost-effectiveness? If

large numbers of individuals are screened, would

one strategy maximize cost-effectiveness and identify the highest number of carriers? This chapter frost

discusses costs associated with CF (medical and

caregiving) and costs associated with carrier screening. It then analyzes the cost-effectiveness of widespread CF population carrier screening under varying assumptions and approaches. This analysis is

necessarily based on modeling; experienced-based

data are lacking.

A CAUTIONARY NOTE

Exarnin ing potential costs and savings associated

with routine CF carrier screening is fraught with

technical and social pitfalls. Some data exist on

attitudes of families with CF children or relatives

toward CF carrier screening, prenatal diagnosis, and

selective abortion (12,31,32). General agreement

exists, however, that the perceptions of the general

population (i.e., those without a relative or close

friend with CF) might well differ from those of

people with family histories of CF, but these

perceptions are less well documented. Some survey

data have been published on what people say they

want and, theoretically, would do (6).

Since OTA found a paucity of experienced-based

data on the attitudes of the general public toward key

factors such as willingness to undergo CF carrier

screening and to terminate CF-affected pregnancies,

OTA calculated cost-effectiveness for several hypothetical scenarios. As explained later in this

chapter, OTA attempted to construct the alternatives

based on three sources: population survey data

specific to CF carrier screening; survey data on the

public’s attitudes toward genetic tests, generally;

and data from privately funded CF carrier screening

pilots.

Aside from uncertainty about reproductive decisionmaking related to CF carrier screening, the costs

of CF, itself, are uncertain and variable. As described in chapter 3, CF’s clinical course varies

widely from person to person; hence, so do medical

costs. Even data on ‘average’ medical costs are less

than optimal. The effect of new pharmaceuticals,

such as DNase, cannot be measured because data

related to their cost or potential to extend median life

expectancy do not exist. While new treatments

might be expensive, they could be quite successful,

with the percentage of women choosing to terminate

affected pregnancies shifting dramatically. This

chapter examines, to a limited extent, the effect on

health care costs if lifespan is extended using current

“average’ expenses. It does not speculate on how

much new pharmaceuticals or gene therapy might

cost, nor the effect their availability might have on

how individuals make decisions about screening and

subsequent reproductive alternatives.

Most importantly, nearly 10 years ago, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral

Research concluded the fundamental value of CF

carrier screening lies in its potential for providing

people with information they consider beneficial for

autonomous reproductive decisionmaking (25). Thus,

while economic analyses can help inform resource

allocation issues surrounding genetic screening,

they have limits. In the context of public policy, the

President’s Commission articulated solid guidance

about the benefits and limits of cost-effectiveness

and cost-benefit analyses for genetic screening:

These analyses are tools to be used within an overall

policy framework, not solely as a method of making

or avoiding judgment.

OTA concurs that the value of CF carrier screening is in information gained. No one can place a

value on having information. Similarly, valuing

births as parents likely value them is speculative, at

best. Thus, personal considerations likely outweigh

societal considerations of cost-effectiveness. Here

an estimate of the impact of CF carrier screening on

-213-
214 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

systemwide health costs is sought; there is no

intimation that something that saves or costs money

is more or less desirable from a welfare standpoint.

COSTS OF CYSTIC FIBROSIS

The cost of any illness is the answer to the

hypothetical question: If the disease disappeared and

everything else stayed the same, how much more

output (valued in dollars) would be available to the

economy? One part of the calculation to ‘answer this

question involves the direct medical costs related to

CF. Costs used in this chapter represent estimated

charges for treating the average person with conventional strategies.

In addition to direct medical costs, disease has

other manifestations. If the condition could be

eliminated, then CF-specific costs of caring for

persons with CF by parents, spouses, or friends

could be avoided. Such nonmedical direct costs are

included in this analysis.

OTA does not consider other dimensions of

benefits and costs that might be included. For

example, eliminating or ameliorating disease reduces premature death and permits people to work or

carry on normal activities, producing a benefit in

terms of future lifetime earnings. OTA does not

recognize these benefits in this chapter, but some

analysts would include this benefit to the economy

in a cost-benefit analysis (the human capital approach) ( 11,22).

Conversely, anxiety and anguish for parents,

fiends, and patients could be counted a cost of

illness, although it is almost never included in

calculations because of difficulty in assigning a

dollar value to such elements. Similarly, a decision

to avoid childbearing as a result of CF carrier

screening could be included as cost due to lost

productivity from any unaffected children who

might otherwise have been born (again, a human

capital approach)-i.e., when couples choose CF

carrier screening to avoid childbearing, society is

made worse off by their decision to avoid conception

because the output from unaffected children they

might have had is lost. Yet, some parents will almost

certainly choose to avoid conception, and a societal

human capital approach is inappropriate for analyzing costs and savings of avoided births for individual

families. It is far from obvious that the value

associated with children born with or without CF

provides any measure of the value of CF carrier

screening to any real person.

Some estimates of the total cost of CF exist, but

include indirect costs associated with lost productivity (10, 11,2 1,22). In this chapter, OTA does not

account for the present value of earnings that a

(potential) child (with or without CF) might contribute to the economy. On a conceptual basis, OTA

adopts a conservative approach, valuing only CFrelated costs, rather than including future market

earnings or non-CF medical costs for either affected

or unaffected individuals.

Medical Direct Costs

Estimating savings that might result from CF

carrier screening requires an estimate of present

value lifetime costs of the disorder. Several groups

have compiled figures on the annual costs for

medical services obtained by persons with CF

(8,33). Hospitalization, CF clinic use, physical

therapy, and drugs account for most CF-related

medical costs. Calculations indicate annual costs of

medical care, projected to 1989 using the Consumer

Price Index, range from about $9,000 to nearly

$14,000 (table 9-l).

OTA uses estimated “annual costs for CF of

$10,000, based on exrarnining medical expense data

from these other sources (22). Assurning an average

life expectancy in 1990 of 28 years, an average

expense of $10,000 per year, and using a 5 percent

discount rate, the net present value of estimated

lifetime medical expenses would be $148,981 (1990

dollars).

Using $10,000 for average annual medical costs

might be an underestimate, but it is generally

consistent with the estimates reported in table 9-1.

| For example, data from a 1989 Cystic Fibrosis

Foundation (CFF) survey provide measures of

hospital and clinic use (8). The average number of

outpatient visits to CF centers was 3.9; at an

assumed cost of $200 per visit to CF centers, such

visits add up to $800 if four visits are made per year

(33). Hospital stays for CF-related reasons averaged

8 days; at an average hospital cost of $700 per day,

hospital costs for CF are about $5,600 per year. The

final major expenses are drugs, including at-home

intravenous antibiotics for about 10 percent of

patients, and physical therapy. A reasonable estimate of such costs is approximately $5,000 per

patient per year (33). Thus, average medical ex-
Chapter 9--Costs and Cost-Electiveness ● 215

Table 9-l—Estimated Average Annual Medical

Expenses for Cystic Fibrosis Treatment

Average annual expense

per patient Source

8,098 (1985)

9,220 (1 989)’

12,300 (1989)

11,400 (1989)

$7,500 (1980) M.V. Pauly “The Economics of Cystic

13,870 (1 989)’ Fibrosis,” Textbook of Cystic Fibrosis,

J.D. Lioyd-Still (cd.) (Boston, MA: PSG,

Inc., 1983), using data from Cystic Fibrosis Foundation, Cystic Fibrosis Patient

Registry, 1980: Annual Data Report.

Cystic Fibrosis Foundation, Cystic Fibrosis Patient Registry, 1983: Annual Data

Report.

M.V. Pauly, “Cost-Effectiveness of Screening for Cystic Fibrosis,” contract document prepared for the U.S. Congress,

Office of Technology Assessment, August 1991, using data from Cystic Fibrosis Foundation, Cystic Fibrosis Patient

Registry, 1989: Annual Data Report.

10,885 (1 989-90) M.V. Pauly, “Cost-Effectiveness of Screening for Cystic Fibrosis,” contract document prepared for the U.S. Congress,

Office of Technology Assessment, August 1991, using data from Wikerson

Group, Inc., Annual Cost of Care for

Cystic Fibrosis Patients (New York, NY:

Wilkerson Group, Inc., 1991).

Office of Technology Assessment, 1992,

based on M.V. Pauly, “Cost-Effectiveness of Screening for Cystic Fibrosis—

Addendum” contract document prepared

for the U.S. Congress, Office of Technology Assessment, February 1992.

penses in 1989 for CF-related care using these

assumptions is about $11,400 per person with CF.

Another set of direct medical costs has been

calculated based on interviews with CF patients’

families and clinicians (33) (table 9-2). This estimate

characterizes individuals with CF as ‘‘mild’ (one

inpatient episode every 2 years), ‘ ‘moderate’ (two

episodes per year), and ‘‘severe’ (four or more

episodes per year). Data from the 1989 CFF survey

describe the distribution of hospital episodes, which

are then used to categorize the number of persons in

each of these categories. Similarly, average numbers

of outpatient visits, pharmaceutical costs, and other

medical expenses are estimated for each patient

population. Examining average medical expenses

based on data in table 9-2 requires one adjustment,

however.

Even if all CF patients were ‘ ‘mild, ’ the expected

number of persons with no episodes would be no

Table 9-2—Annual Cost of Medical Care

for Cystic Fibrosis Patients

Treatment Mild Moderate Severe

Acute treatment

Antibiotics. . . . . . . . . . . . . . $ 2,000a

IV supplies. . . . . . . . . . . . . 300

Hospitalization. . . . . . . . . . 3,500

Miscellaneous. . . . . . . . . . . 100

Total cost acute. . . . . . . . . 5,900

Chronic management

Visits to CF Center. . . . . . . 600

Medications. . . . . . . . . . . . . 2,000

Total cost chronic. . . . . . . . 2,600

Total cost acute and

chronic treatment. . . . . . 8,500

$6,000

500

14,000

200

20,700

800

3,000

3,800

24,500

$12,000

900

28,000

400

41,300

1,200

4,000

5,200

46,500

greater than 50 percent; in fact, it was 61 percent.

Thus, there is another category, “submild,” whose

illness requires infrequent hospitalization. If approximately 40 percent of patients were submild and 40

percent were mild, about 60 percent of persons

would not be hospitalized and 20 percent would be

hospitalized once. About 13 percent of all patients

had two or three episodes per year; this group

represents the ‘ ‘moderate’ portion. Finally, about 6

percent of all patients had four or more hospitalizations per year and comprise the “severe” patient

group. Medical expenses in table 9-2 need to be

adjusted to account for the ‘‘submild’ group (22).

No data exist on the average expenses of “submild’ persons with CF, but a reasonable assumption

might be their expenses are about twice the average

medical care cost of the average American under 65

years of age, or $2,000 (22). In fact, costs might be

slightly higher. Actual costs for one submild case

(parents providing physical therapy and no hospitalizations in 9 years) were approximately $4,700 in

1990; the cost of drugs alone was $1,900 (23).

Nevertheless, erring on the conservative side ($2,000),

the estimated average annual medical costs when the

proportion of individuals with submild, mild, moderate, or severe cases of CF is accounted for yields

a second estimate of annual medical costs at

$10,885.

Nonmedical Direct Costs

The chief nonmedical direct cost of CF is family

caregiving time. CF centers estimate parents need to

spend about 2 hours per day on therapy for a child

with CF (730 hours per year) (22); many families
216 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

have therapists provide chest physical therapy (23).

In addition, parents, spouses, or other family members lose time from work or housework when an

individual with CF misses school or work.

It is difficult to obtain direct estimates of the

number of sick days for people with CF—and hence

the nonmedical (caregiving) direct costs to family

members-because the severity varies considerably

across patients and over time. The OTA analysis

assumes 20 sick days per CF patient per year,

involving 8 hours per day of work or housework

missed (160 hours per year). Nonmedical direct

costs also must account for time spent taking the

person with CF to medical appointments. The

average number of hospital days is eight (8,33), and

OTA assumes 4 hours of caregiving time are

associated with each hospital day (32 hours per

year). Time also is spent on physician and clinic

visits not associated with an acute episode. The

frequency of such visits is assumed to be four per

year, at a time cost of 4 hours (16 hours per year).

The total number of hours per year for CF-related

caregiving is estimated to be 938.

OTA assumes caregiving time costs an estimated

domestic/nursing wage of $10 per hour. While no

empirical work supports this value, it is taken to be

reasonable. Overall, then, the present value of

lifetime nonrnedical direct costs associated with CF

is estimated at $139,744 (assuming an average life

expectancy in 1990 of 28 years and using a 5 percent

discount rate), This chapter presents only data using

$10 per hour as the cost for time associated with

nonmedical direct costs. Using a value that is 30

percent lower changes the relative cost-effectiveness

less than changing other parameters, such as reproductive behavior or test sensitivity. It can be an

important assumption in scenarios that are borderline net savings, however, since savings decrease.

COSTS OF CARRIER SCREENING

FOR CYSTIC FIBROSIS

Since CF is the most common recessive genetic

disease among American Caucasians of European

descent, there is intense commercial interest in

marketing CF mutation assays. At least six commercial companies currently market CF carrier tests and

at least 40 university and hospital laboratories

conduct CF carrier assays. Table 9-3 lists a sample

of prices for commercial facilities and university and

hospital laboratories. The number of mutations

Table 9-3-Costs for Cystic Fibrosis Carrier Tests At

Selected Facilities

Institution Price per sample

Baylor College of Medicine. . . . . . . . . . . . . . . . .

Boston University. . . . . . . . . . . . . . . . . . . . . . . . .

Collaborative Research, Inc.. . . . . . . . . . . . . . . .

Cornell University Medical Center. . . . . . . . . . . .

GeneScreen. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genetics & IVF Institute. . . . . . . . . . . . . . . . . . . .

Hahnemann University. . . . . . . . . . . . . . . . . . . . .

Hospital of the University of Pennsylvania. . . . .

Integrated Genetics. . . . . . . . . . . . . . . . . . . . . . .

Johns Hopkins University Hospital... . . . . . . . .

Mayo Medical Laboratories. . . . . . . . . . . . . . . . .

St. Vincent’s Medical Center., . . . . . . . . . . . . . .

University of Minnesota. . . . . . . . . . . . . . . . . . . .

University of North Carolina. ......., . . . . . . . .

Vivigen, Inc.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

$55 or 200

170

173

75

165

225

225

150

150

270

200

150

136

150

200 to 220

SOURCES: Office of Technology Assessment, 1992, and M.V. Pauly,

“Cost-Effectiveness of Screening for Cystlc Fibrosis,’’ contract

document prepared for the U.S. Congress, Office of Technology Assessment, August 1991.

assayed differs from facility to facility, and test costs

reflect this variation. Additionally, some quoted

prices include costs of pretest education and posttest counseling, while others do not. Costs of tests

reflect differential royalty license fees among the

facilities for patents related to the CF tests, as well

(box 9-A). Nevertheless, the average charge for CF

mutation tests among these facilities is approximately $170.

Photo credit: University of Kansas Medical Center

H.C. Miller Building, University of Kansas Medical

Center. University medical centers, as well as

commercial companies, perform CF mutation analyses

for testing and screening purposes.
Chapter 9---Costs and Cost-Effectiveness ● 217

Box 9-A—Licensing of Polymerase Chain Reaction

The polymerase chain reaction (PCR) allows minute quantities of an identical sequence of DNA to be

replicated millions of times (ch. 4); it is a critical tool for the CF mutation test and virtually all other new DNA-based

diagnostic procedures. In 1987, Cetus Corp. received a patent for PCR. Currently, patent rights for PCR diagnostics

are held by Hoffmann-La Roche, Inc. Because PCR is used in so many current and potential genetic tests, the terms

of PCR licensing agreements are important determinants of future costs of tests to consumers.

Shortly after Hoffrnann-La Roche acquired patent rights for PCR, commercial and hospital laboratories

expressed concern that the proposed fee structure would discourage some laboratories from seeking agreements.

For example, the terms for commercial facilities would have amounted to roughly 15 percent of the cost of each

test that was performed. Any new applications-e. g., for a different diseas---that a laboratory wanted had to be

approved by Roche. Such licensing terms might have had a chilling effect on diagnostic companies and hospital

laboratories that perform molecular diagnostics. Costs of DNA-based analyses, in general, would likely have risen

rather than decreased as many expected they would with greater numbers of tests and increased volume.

Hoffmann-La Roche, Inc. announced in February 1992 that a new company, Roche Molecular Systems, had

been formed to handle the development of PCR. The new licensing agreement announced includes permission to

use PCR for a broad range of applications. Licenses will be available to all academic and commercial laboratories

who request them, and academic and nonprofit licenses will require no down payment or minimum royalty

payments and a royalty rate of less than 10 percent.

The saga of PCR licensing illustrates the importance of patents to future costs of DNA-based diagnostic tests,

but the intellectual property issue is not solely conffined to the PCR patent. Patents for the CF gene and its mutations,

for example are pending. Thus, while automation will likely lower costs of DNA diagnostics, intellectual property

protection to some extent might counter lower prices. Royalty licensing fees from patents will be reflected in charges

for the tests to consumers. Resolving debates surrounding the Human Genome Project and intellectual property will

have important consequences for ultimate cost—and hence, utilization and cost-effectiveness-of DNA-based

diagnostics.

SOURCES: Office of Technology Assessment 1992; based on M. Hoffmann, “Roche Eases PCR Restictions,” science 225:528, 1992; and

D. McQuil.kew Roehe Molecular Systems, Inc., personal communications, January 1992, February 1992.

OTA uses a lower cost per test--$100 per test’s availability and to educate them about CF

person—in its base case and most other analyses to carrier screening. No estimates exist for costs related

reflect the expectation that test costs will likely

decrease as CF carrier screening becomes routine;

many believe economies of scale will be possible

with larger volumes of screening assays. This cost

includes the test itself and post-test counseling, but

not pretest education or marketing. The $100 per

individual cost ($200 per couple) also assumes all

couples require the same amount of post-test counseling (and therefore incur an equivalent cost). In

fact, couples who both screen negative (-/- couples)

are likely to require far less post-test counseling than

couples where one screens positive and one screens

negative (+/- couples) or couples whose results are

both positive (+/+ couples), but no assumptions are

made about such variation. OTA also presents

scenarios with higher and lower costs per test.

Three other components were included in testrelated costs of CF carrier screening. First, some

expenses will be incurred to inform people about the

to providing such information and services. OTA

uses a value of $25 per initial screening contact as

the pretest cost of information and education (22).

Some argue $25 far exceeds what should be

assigned to this cost—that most individuals will be

visiting their physician for other purposes and that

promotional pamphlets, videos, or mailings should

constitute the sole cost of information services. OTA

posits, however, that even if physicians include the

cost of informing patients as part of their standard

charge for a visit, this does not mean that providing

information is costless—it consumes physician time

and office space. Attaching a cost of $100 per hour

to physician time and office use (equivalent to gross

revenues of $200,000 per year), and assuming

furnishing information takes 10 minutes, the cost per

person informed would be about $17. TO account for

additional expenses related to nonphysician time

and promotional materials, OTA uses a total cost of
218 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

pretest information and education of $25. No charge

is assessed for people who do not elect screening,

although such individuals might well receive some

pretest information. Similarly, although most scenarios considered here involve screening the woman

frost followed by the male only if she is positive, no

charge is assessed for informational costs of screening the partner of those 1 in 25 women who test

positive (would increase total cost of screening, but

not significantly). Thus, others will argue OTA

underestimates the total cost of pretest expenses. As

results of the analysis show, the total cost associated

with performing CF carrier assays is sensitive to

assumptions about this charge; further research on

actual expenditures related to it is warranted.

Second, because prenatal testing will be part of

CF carrier screening when +/+ couples decide on

childbearing, the cost of chorionic villus sampling

(CVS) is relevant. CVS charges in two northeastern

medical centers were investigated (22). As for other

procedures, the specitics of what was included at

what price varied. CVS sampling and the cost of a

CF mutation analysis is priced at $1,200 in this

analysis. Third, the cost of an abortion is priced at

$900 (22).

KEY VARIABLES AN D

ASSUMPTION S

As just described, the cost of CF carrier screening

includes providing pretest information and education, the actual test cost, post-test counseling,

prenatal testing, and abortion. Beyond direct costs

associated with performing CF carrier analyses,

however, other key parameters that affect the

economic analysis include:

●

●

●

●

sensitivity of the CF test;

percent of individuals who voluntarily elect to

determine their CF carrier status;

family size, percent who alter their reproductive behavior, and how the behavior is

altered; and

screening approach=. g., preconception versus postconception, or women first, followed

by men only for positive women, versus

couples.

The following sections present the assumptions or

values used for each of these factors in OTA’s base

case. Later sections describe how costs and savings

were calculated, and how the assumptions or values

for each were varied singly or in combination.

Test Sensitivity

As described in detail in chapter 4, CF mutation

analyses using delta F508 and an additional 6 to 12

mutations (DF508+6-12) detect about 85 percent of

CF carriers, although depending on ethnic background and the battery of mutations used, test

sensitivity can approach 90 percent (3,20). In

Ashkenazic Jews, DF508+6 identifies nearly 95

percent of carriers (27). OTA uses 85 percent

sensitivity in the base case and in most alternative

scenarios, but varies the sensitivity in some scenarios to demonstrate its affect on costs and savings.

Participation

What percent of eligible individuals will elect to

be screened for their CF carrier status? Estimates are

available for individuals with family histories of CF

(12,18,31), as well as for one general population

sample from a midwestem urban hospital and

suburban health maintenance organization. A survey

of this latter population found 84 percent of respondents had a strong interest in CF carrier screening

before pregnancy and 69 percent would avail themselves during a pregnancy (6). Other surveys measure the acceptance of the general American populace

toward prenatal genetic tests (28,30) and carrier

screening (30), although not specific to CF. According to both these surveys, just over 80 percent of

Americans say they would avail themselves of such

tests.

To what extent, however, do such surveys represent real-life decisions? The key data would come

from knowledge about what percent of individuals

participate in CF carrier screening, but to date no

published data exist. Early results from privately

funded pilots, however, offer insights into what

participation rates realistically might be expected.

Through March 1992, 78 percent of participants

(Caucasian Americans of European descent or

Hispanic ethnicity) in a California pilot study have

elected CF carrier screening (34); these individuals

do not pay for their tests. Out-of-pocket costs

dramatically affect the percent of people electing CF

carrier screening: a Texas study reveals participation

dropped from about 80 percent to 20 percent when

a pilot ended and charges for screening began (3).

OTA uses 80 percent in the base case. Some might

argue such a level is too high, despite experience

from pilot projects. On the other hand, while the 80

percent figure will likely exceed participation in CF
Chapter 9--Costs and Cost-Effectiveness ● 219

carrier screening’s early phases of dissemination, it

does not seem unreasonable in light of current

steady-state data on the percentage of pregnant

women who voluntarily elect prenatal testing for

maternal serum alpha-fetoprotein or prenatal genetic

analysis due to advanced maternal age (34): For both

tests, 80 percent accept the procedure(s). OTA also

examine“s , however, a participation rate of 20

percent, in light of OTA survey results that most

third-party payers say they are unlikely to currently

pay for CF carrier tests without a family history (ch.

7). Nevertheless, should CF carrier screening be

incorporated into routine obstetric practice, thirdparty payment will likely increase, out-of-pocket

expenses decrease, and participation increase. OTA

also models 50 percent participation.

The population from which the 100,000 women or

couples is drawn is assumed to be one for which the

overall test sensitivity is at least 85 percent and the

carrier frequency is 1 in 25. A more accurate

approach might be to adjust the pool for racial and

ethnic demographics. Different attitudes toward

genetic screening and reproductive behavior prevail

and would complicate the calculations. Further, the

frequency of newborns with CF within other populations is so low+. g., 1 in 17,000 (4) to 19,000 (16)

African American newborns, 1 in 9,600 Hispanic,

and 1 in 90,000 Asian American babies (16)---that

weighting a random sample would have little net

effect.

Finally, the pool is presumed to consist only of

individuals who contemplate having children. Some

argue CF mutation analysis would be of little interest

to those choosing to be childless, although people

who do not intend to have children sometimes do.

Similarly, arguments can be made that some who do

not contemplate children still might seek CF carrier

screening solely for informational purposes or because of its impact in informing their relatives.

Reproductive Behavior

Fundamental to the cost-effectiveness analysis of

CF carrier screening is reproductive behavior. First,

the analysis in this chapter assumes all couples (+/+,

+/-, and -/-) seek the current U.S. average of 2.1

children per family (24). Some research indicates

that families who have a child with CF alter their

reproductive behavior by having fewer children

(12,18,32), but these are retrospective analyses. No

data exist for the total number of children that

couples might ultimately have after identification as

+/+ in the absence of a child with CF.

Second, only changes in the reproductive behavior of +/+ couples are modeled, Clearly, +/- couples

might choose to avoid conception, seek prenatal

testing, or consider pregnancy termination of carrier

fetuses because current tests are not 100 percent

sensitive, and hence there is some chance a fetus

identified as a carrier actually has CF. Results from

privately funded pilot studies, however, reveal no

such decisions to date (2,26) (ch. 6).

Third, specific assumptions are necessary for

precisely how people alter their reproductive behavior once they are identified as +/+ couples. The base

case uses an infertility frequency in the general

population of 8.4 percent (19,29). Of fertile couples,

10 percent is used as a reasonable estimate of the

fraction of +/+ couples who will avoid conception

(3). Avoiding conception obviously incurs costs, but

fertile couples are also likely to incur contraception

costs over their reproductive lives, and so contraception or sterilization costs are not included in this

analysis.

Assumptions about the reproductive behavior of

+/+ couples are critical to the cost analysis of

population carrier screening for CF. The base case

assumes all of the remaining 90 percent of+/+ fertile

couples become pregnant and seek prenatal testing

and that all couples with affected fetuses opt to

terminate the pregnancy. Alternative scenarios vary

the proportion of +/+ couples seeking or declining

prenatal testing and the percentage electing abortion

of CF-affected fetuses. Again, limited data exist on

reproductive behaviors as they relate to CF carrier

screening in the general population. less than 20

CF-affected fetuses have occurred in pilot studies; in

one study in Texas, 7 of 14 affected pregnancies

were terminated (3). In the attitudinal survey of

midwest urban and suburban women, 29 percent

said they would terminate a pregnancy if the fetus

were found to have CF (6). (As described in chapter

5, data from families of children or relatives with CF

have been reported (18,3 1,32), but those data are not

thought to be wholly representative of the general

population.)

Screening Strategies

Should both a man and woman be screened as a

couple, or should the man be screened only if the

woman’s results are positive? Should the negative
220 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

partner in a +/- couple be screened for additional

mutations to detect a higher proportion of carriers?

Is there an effect on cost whether screening is

preconception or postconception? The strategy employed in a CF carrier screening protocol affects

costs and savings.

If the CF mutation assay detected 100 percent of

mutations, it only would be necessary to screen one

partner-usually the woman-because paternity is

never assured. Placing primary focus on women is

objectionable to some, however (14,15). Additionally, men and women are not always linked as a unit

through their reproductive lives. Finally, limiting

carrier screening to only men who are partners of

positive women loses the opportunity to identify

male carriers for whom CF carrier status might be of

personal interest or future importance-to them and

their relatives. On the other hand, from a cost

perspective, it is clear the total number of individuals who will be screened in a “woman, then man”

strategy will be less thanina‘‘couple’ strategy, and

hence CF-related screening costs will be less—but

to what extent?

Strategies for CF carrier screening can be preconception or postconception. The analysis in this

chapter examines preconception screening. Modeling a postconception strategy is difficult because,

although much CF carrier screening is of pregnant

women and their fetuses, such screening is offered

because the patients are being seen for other prenatal

or genetic services+. g., advanced maternal age or

a family history of another disorder. Modeling

reproductive behavior would be more complex

because it becomes confounded by results for these

other tests. Nonpaternity might be expected to be a

greater factor in postconception CF carrier screening. Some fraction of postconception individuals

will receive test results of an affected fetus in the late

stages of pregnancy, where termination might not be

feasible, which could then affect subsequent decisions about total family size.

Cost estimates for preconception strategies that

screen only women frost, as well as the strategy of

screening couples, are presented. (The base case

involves the former.) The analysis also examines the

effect on costs and savings of screening the negative

partner of +/- couples for additional mutations to

detect a higher proportion of carriers. OTA assigns

no additional cost for the followup analysis because

at least three institutions follow such a protocol and

do not charge extra for the additional mutations

tested (3,9,34).

COSTS AND SAVINGS

The analysis models a steady-state equilibrium, in

which CF mutation analysis is available to all

prospective parents at the outset of their reproductive planning-i. e., before the birth of any children.

This assumption incorporates the fact that identification of CF carrier status affects all subsequent

pregnancies.

Costs With No Carrier Screening

At a carrier frequency of 1 in 25, 160 of 100,000

couples would be +/+, and be at 1 in 4 risk of having

a child with CF in each pregnancy. Of these couples,

13.4 would be infertile (0.084x 160). The remaining

146.6 couples each would have, on average, 2.1

children, of which 0.53 would theoretically have CF.

Overall, the total lifetime CF-related medical costs

without CF carrier screening are $11,575,536 (0.53

children/couple x$148,98 1 lifetime medical spending

child x 146.6 couples). Total nonmedical direct costs

are $10,857,782 (0.53 children/couple x $139,744

lifetime CF-related caregiving costs x 146.6 couples). Total direct costs systemwide in the absence

of screening are $22,433,318.

In fact, 36.7 couples of the 146.6 preconception

couples will have a child with CF for their first

pregnancy. As a result, some of these couples will

alter their reproductive behavior (12,18,31,32) and

avoid further conception (thereby saving potential

costs associated with having an affected pregnancy

in the future-i. e., cost offsets). Others will seek

prenatal tests and consider abortion in subsequent

pregnancies (thereby adding costs, but if abortion is

chosen, contributing cost offsets). overall, however,

the net effect on total direct costs of altered

reproductive behaviors for the 36.7 couples in the

absence of DNA-based CF mutation analysis is

negligible.

Calculating Costs

The ways in which costs were calculated for the

base case are presented in this section for illustrative

purposes (table 9-4). Calculations for the alternative

scenarios are not presented, but were performed in

the same manner. Again, the base case involves the

following:
Chapter 9---Costs andCost-Electiveness . 221

Table 9-4-Costs, Cost Offsets, and Net Savings for Base Casea

costs Cost offsets (savings)

cost of Total CF

CF carrier carrier Total Medical plus

screening per screening Total medical caregiving caregiving

Description Number couple costs savings savings savings

Woman tests negative, ., . .........77,280

Woman tests positive, man

tests negative. . . . . . . . . . . . . . . . . 2,627.5

Woman tests positive, man

tests positive. . . . . . . . . . . . . . . . . . 92.5

Infertile. . . . . . . . . . . . . . . . . . . . . 7.8

Fertile, voluntary childless. . . . . 8.5

Fertile, prenatal testing, and

abortion. . . . . . . . . . . . . . . . . . 76.2

Total cost of CF carrier screening. . . —

Total caregiving and medical

offsets. . . . . . . . . . . . . . . . . . . . . . . . —

Net savings per 100,000

couples. . . . . . . . . . . . . . . . . . . . . . .

Net savings per 100,000

couples. . . . . . . . . . . . . . . . . . . . . , —

$125

225

—

225

225

4,215

—

—

$9,727,500

591,188

—

1,755

1,913

321,183

10,643,539

—

—

o

0

6,018,832

—

o

0

5,645,658

—

o

0

11,664,490

—

12,963,753

2,320,214

pregnancies.

SOURCE: Office of Technology Assessment, 1992.

●

●

●

●

●

●

●

lifetime direct CF medical costs of $148,981

and lifetime CF-related caregiving costs of

$139,744 per child with CF;

carrier frequency of 1 in 25;

100,000 preconception women are screened,

followed by screening the partner if the woman

is positive;

$25 cost per initial screening contact; test cost

of $100 per test performed; and test sensitivity

of 85 percent;

2.1 children per couple regardless of test

results;

8.4 percent infertility and 10 percent of fertile

+/+ couples choose to avoid conception; and

80 percent who are offered CF mutation analy -

sis - participate, all +/+ fertile couples seek

prenatal testing (CVS at a cost of $1,200 per

pregnancy) (22) and termin ate all affected

fetuses ($900 per pregnancy) (22).

Of 100,000 women offered screening, 80,000

elect to participate. Of these 80,000 women, 2,720

carriers are identified and so 2,720 men are tested.

Of these, 92.5 males will be identified as carriers,

and hence 92.5 +/+ couples are identified and

2,627.5 receive results indicating they are +/-. In

fact, among these +/- couples are 16.3 +/+ couples

who are missed, of whom 14.9 are fertile. Of the 92.5

+/+ couples who are identified, 7.8 are infertile

(0.084 x 92.5) and 8.5 are voluntarily childless (0.10

x [92.5-7.8]). Thus, 76.2 fertile couples seek prenatal

testing. Finally, 51.2 +/+ couples are missed (46.9

me fertile), among the 20,000 women who elected

not to participate or who were undetected because

the test is 85 percent sensitive, not 100 percent.

The cost per woman screened is $125 ($25 pretest

for information and education + $100 for CF

mutation analysis and post-test counseling). Women

with negative results do not incur additional costs for

screening. For identified carriers, there is an additional cost of $100 for CF mutation analysis and

post-test counseling for the man, for a total of $225

per couple. This cost applies to couples who are

identified as +/-, couples who are +/+, but infertile,

and +/+ couples who decide not to have children. For

+/+ couples who chose to conceive, costs are $225

plus the additional cost of prenatal screening and

abortion. Since these couples seek a final family size

of 2.1 children, a theoretical 2.8 pregnancies must be

undertaken and 0.7 abortions per couple performed.

Therefore prenatal screening and abortion costs add

$3,990 per couple ($1,200 x 2.8 + $900 x 0.7).

Screening related costs per +/+ couple, then, are

$4,215 ($25 + $100+ $100+ $3,990).
222 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

The total cost related to performing CF carrier

screening for this base case is $10,643,539.

Calculating Cost Offsets

Two types of systemwide cost offsets (i.e.,

savings) flow from CF carrier screening: avoiding

direct medical costs and avoiding nonmedical direct

costs associated with time for caregiving. The

benefit calculations that follow are a means to

examine systemwide economic effects from CF

carrier screening, not to positively or negatively

reflect the intrinsic or extrinsic value to any individual or couple.

Neither medical nor caregiving cost offsets flow

from infertile couples. The voluntarily childless

couples, however, avoid medical and caregiving

costs. Of 2.1 total expected children, 0.53 with CF

would be expected per couple; overall, 4.5 CFaffected births would be avoided for this population

(8.5 couples x 0.53 affected births/couple). Total

medical cost offsets from those choosing to be

childless are $670,415 ($148,981 per birth x 4.5

births). Savings from caregiving cost offsets for this

group are $628,848 ($139,744 x 4.5).

Similarly, cost offsets arise from +/+ couples who

use prenatal testing and, in the base case, terminate

all fetuses diagnosed with CF. Some 40.4 affected

births are avoided (76.2 couples x 0.53 affected

births per couple). Total medical cost offsets for this

group are $6,018,832 ($148,981 per birth x 40.4

births); total caregiving offsets are $5,645,658, Total

medical and caregiving savings---costs avoided—

are $12,963,753.

Because the test is less than 100 percent sensitive

and because 20,000 women elect no screening, some

+/+ couples are missed and some children with CF

are born. Thus, the costs avoided fall short of the

$22,433,318 spent in the absence of CF carrier

screening. Overall, 77.7 babies with CF would be

expected in the base case from the pool of 100,000

couples (146.6 fertile +/+ couples x 0.53 children

with CF/couple), but 49.9 affected births are avoided

(4.5 + 40.4). Systemwide, $12,963,753 are saved,

but $10,643,539 are spent on screening, for a net

savings over no screening of $2,320,214. That is, in

the base case, sufficient savings accrue from avoided

medical and caregiving costs to pay for costs

associated with screening.

Alternative Scenarios

Costs and savings for several alternative scenarios

were developed. Table 9-5 presents the base case

and 14 representative scenarios that demonstrate the

effects of varying price, participation, test sensitivity, reproductive behavior, and screening strategy (a

strategy that screens partners of positive women

with a more sensitive test (90 percent) and a couples

strategy).

Six alternative cases actually yield sufficient

savings from avoided medical and caregiving costs

to pay for all costs associated with screening—

scenarios A, B, E, F, G, and J. All but scenario J,

however, include the unlikely assumption of 100

percent termination of affected pregnancies. These

scenarios are presented for illustrative purposes only

or to examine the effect of other variables on

cost-effectiveness, not as representations of likely

occurrences or a goal to be achieved.

Scenario J also yields net economic savings over

no screening from a systemwide perspective. It

assumes 80 percent participation, a goal that might

be achieved if CF carrier becomes as accepted as

other prenatal tests (34) or as in the pilot studies in

California and Texas described earlier (2,34). However, unlike in these pilots, a cost per test of $75 is

assumed; participants in the pilots are/were not

charged, and it is known that participation declines

when out-of-pocket costs rise (2). Finally, scenario

J assumes 64 percentl of affected fetuses detected

are terminated, which could well be more frequent

than will actually occur.

The remaining eight scenarios (C, D, H, I, K, L,

M, N) do not yield net savings on a systemwide

basis—i.e., they cost more than if no screening

exists. As discussed below, several factors account

for why population CF carrier screening is not

cost-effective under assumptions used in these

scenarios.

1 Eighty percent of +/+ couples undergo prenatal diagnosis, and the remaining 20 percent choose no prenatal diagnosis because they would not

consider terminating an affected pregnancy, regardless of outcome. The parents of 80 percent of affected fetuses diagnosed through the prenatal test elect

to terminate, but 20 percent do not. This latter group might have sought prenatal testing with the thought of terrninating, but then chose not to. Or they

might have chosen premtal testing knowing they would not terminate, but wanted information to prepare for the birth of a child with CF. The net

frequency of abortion is 64 percent after combining the split decision process-i. e., that some will not seek any prenatal testing, but others might (which

costs the system), but then opt not to terminate an affected pregnancy (also adds costs).
Chapter 9--Costs and Cost-Electiveness ● 223

Table 9-5—Effect of Assumptions on Net Savings Over No Screening

Percent Percent

+/+ +/+ Net

who seek who abort systemwide

Test sensi- Cost prenatal affected savings compared

tivity (O/.) per test Participation testing pregnancies to no screening

Base case. . . . . . . . . . .

A . . . . . . . . . . . . .

B . . . . . . . . . . . . .

c . . . . . . . . . . . . .

D . . . . . . . . . . . . .

E . . . . . . . . . . . . .

F . . . . . . . . . . . . .

G . . . . . . . . . . . .

1-f . . . . . . . . . . . . .

I . . . . . . . . . . . . .

J . . . . . . . . . . . . .

K . . . . . . . . . . . . .

L. . . . . . . . . . . . .

M . . . . . . . . . . . .

N . . . . . . . . . . . . .

85

100

85

85

85

85

85

100

85

85

85

85

85190

85

85

$100

100

100

100

100

100

100

100

100

100

75

100

100

100

50

800/0 of 100,000

women; man only

if woman positive

100% of 100,000

women; man only

if woman positive

100% of 100,000

women; man only

if woman positive

80% of 100,000

women; man only

if woman positive

80% of 100,000

women; man only

if woman positive

20% of 100,000

women; man only

if woman positive

500/0 of 100,000

women; man only

if woman positive

800/0 of 100,000

women; man only

if woman positive

20% of 100,000

women; man only

if woman positive

20%0 of 100,000

women; man only

if woman positive

800/0 of 100,000

women; man only

if woman positive

50% of 100,000

women; man only

if woman positive

50% of 100,000

women; if the

woman is positive,

the man is tested

with additional

mutations at 900/0

sensitivity

1OO% of couples

participate

1 00°/0 of couples

participate

100

100

100

100

80

100

100

100

100

80

80

80

80

100

100

100

100

100

50

64c

100

100

100

50

64c

64’

64C

64C

100

50

$2,320,214

9,007,651

2,977,225

(3,456,025) b

(1 ,786,030)

589,498

1,474,375

7,188,877

(840,078)

(430,182)

338,729

(1 ,075,074)

(765,919)

(6,682,775)

(4,077,693)

Effect of Varying Rates of Selective Termination have similar assumptions except the fraction of

affected pregnancies terminated varied —100 perVarying the ratio of those who elect to continue cent and 50 percent, respectively. Net savings per

pregnancies diagnosed with CF to those who elect 100,000 women screened compared to no screening

termination exerts a significant effect on net savings declines from $2,320,214 to -$1,786,030. Scenarios

over no screening. The base case and scenarios D E and H are likewise identical except for the fraction
224 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

of affected pregnancies terminated, and cost savings

are eliminated when the frequency is halved.

Effect of Test Cost

Reduced test costs appear as important as reproductive behavior, especially when participation is

high. Not surprisingly, decreasing the cost of CF

mutation analysis results in increased net savings

(compare scenarios D and J)---to a point where

cost-effectiveness can be achieved when the price

per test is dropped 25 percent under the assumptions

used. Net savings of -$1,786,030 in scenario D rise

to $338,729 in scenario J when the cost per test drops

from $100 to $75 per individual.

Effects of Test Sensitivity or Screening Strategy

Increasing test sensitivity results in net system

savings, if reproductive behavior and other variables

are constant (scenarios A versus the base case, and

scenarios L versus K). And as expected, the strategy

of screening both individuals (scenario M), rather

than only the male when the woman is positive

(scenario B), decreases savings from $2,977,225 per

103,400 total individuals screened for the woman

first strategy ($28.79 saved per person screened) to

-$6,682,775 per 200,000 individuals screened in the

couples strategy (cost of $33.41 per person). Decreasing the cost of screening by 50 percent in the

couples strategy (scenario M versus N) is still not

cost-effective under the assumptions used. But

again, since the primary value of CF carrier screening is information, for which no cost can be

assigned, the informational value to +/- couples

where the male is positive and the female is negative

would be entirely missed in the woman-first strategy.

Effect of Participation

The percent of individuals electing CF carrier

mutation analysis has an effect on system savings,

all other factors being equal. Participation rate is less

important, however, than test cost or reproductive

behavior. In fact, lower participation is more costeffective, depending on test cost or selective termination, because costs associated with screening are

not incurred, although high participation and a high

frequency of termination or low test cost is most

cost-effective. Scenarios D, I, K, and J best illustrate

this point for test cost. The first three scenarios

assume a test cost of $100, 85 percent sensitivity,

and the bifurcated reproductive decision option that

results in a net terrnination of 64 percent of affected

pregnancies; scenario J assumes the same at a test

cost of $75. What differs among the first three is

agreement to be screened—80 percent, 20 percent,

and 50 percent, respectively; scenario J assumes 80

percent participation to compare it to scenario D. At

80 percent acceptance and $100 test cost per 100,000

eligibles, CF carrier screening is not cost-effective

(net cost of $1,786,030), but when test cost is

reduced to $75, CF carrier screening is cost effective

(net savings of $338,729). In contrast, when participation falls to 50 percent and test cost is $100, net

cost drops to $1,075,074; when acceptance is only

20 percent the net cost is $430,182. Scenarios C, E,

and H demonstrate the effect of participation versus

selective termination).

QUALIFICATIONS ON THE

ANALYSIS

Results of this analysis are highly dependent on

the assumptions made. Some of the more critical or

controversial assumptions are highlighted, including:

e

●

●

Agreement to be screened. The results are

sensitive to the proportion of the eligible

population who consent to initial screening, but

less so than reproductive behavior or test

sensitivity. Even with 20 percent participation,

screening can be cost-effective, depending on

the other variables.

Reproductive behavior. Assumptions about

reproductive behavior are the most important

factor in the analysis, but experience-based

data are sparse. How completed fertility is

affected by the occurrence of CF (in the

absence of screening), how the availability of

CF carrier screening affects potential parents’

choices between remaining childless versus

prenatal screening with selective termination,

and how both CF carrier screening and prenatal

testing availability affect final average family

size are critical.

Pretest costs. A cost for marketing CF carrier

screening and for pretest education is assessed

as a screening expense. Although this cost is

small per eligible individual, it is an important

part of the total cost because it is incurred for all

first contacts who elect screening. No data

empirical data exist to support the $25 used.

OTA estimated the value by analogy. While it

might be such costs are higher for those who
Chapter 9---Costs and Cost-Effectiveness ● 225

elect screening, balanced against higher pretest

costs for these individuals is the likelihood of

lower or no costs for those who do not

participate.

. Cost of the CF carrier assay. A cost of $100

per test is assumed in most scenarios, which is

lower than current charges, Using costs of $75

and $50 per test increases net savings. Ultimately, the assay’s cost might be less important

overall to net savings than it is to its impact on

the willingness of individuals to elect screening

if they must pay the cost themselves. Nevertheless, should the cost reach $50 to $75 per

individual, savings are achieved, depending on

the frequency of pregnancy termination.

. Median life expectancy. A median life expectancy of 28 years in 1990 is used. Using a

longer life expectancy increases net savings if

CF-affected births are avoided, but also increases costs of the disease when +/+ couples

are missed because of test sensitivity, when

people elect no screening, and when reproductive behavior is not altered. Overall, the effect

of median life expectancy on costs and savings,

however, is negligible if the other variables in

the analysis are held constant. More importantly, as median life expectancy increases,

individuals might be less likely to alter their

reproductive behavior, which will likely result

in fewer CF-affected births avoided and lower

net savings.

| Present value of avoided CF-related costs.

An estimate of $10,000 as the annual medical

cost per person with CF is used, which is at the

low end of annual cost estimates compiled by

several sources. Higher estimates, however, are

based on calculations that appear to conflict

with actual data on use of care by CF patients

(21,22). Another potentially important adjustment to this estimate is the assumption that the

$10,000 occurs uniformly every year over the

person’s lifetime. As CF patients live longer

and are treated more effectively, the period of

high medical costs likely will be pushed further

into the future. Even if those costs eventually

are substantial, however, they are discounted

back to the present, which means they add little

to the present value of CF-related medical

costs. Conversely, some new treatments and

technologies likely will be expensive. Greater

use of heart-lung transplants or even gene

therapy, for example, will increase CF-related

medical costs—significantly if the therapies

become a common option. The choice of

discount rate is also important.

Paternity. The analysis assumes the prospective father can be identified and screened and

that each woman has the same partner for all

births, so that CF carrier screening need be

done only once per couple. Uncertainty of

paternity already confounds real-world use of

genetic tests, with frequencies of nonpaternity

reported or estimated from 2 to 15 percent

(1,17). People also may have multiple partners

over their reproductive years. Both behaviors

reduce net savings.

Test precision. Any costs (e.g., anxiety) that

theoretically might be imposed by a less that

100 percent sensitive test were unaccounted

for, although post-test costs related to counseling were included. Similarly, psychological

costs associated with false positive findings—

most likely from laboratory handling error—

were also unaccounted for, since evidence

indicates DNA tests per se yield accuracy

greater than 99 percent (5,13). False positive

findings would not result in a CF-affected

pregnancy, but could result in the cost of a

prenatal test for a fetus not actually at risk.

Preferential screening of relatives of carriers. Although no specific scenario is examined,

close relatives of carriers might seek and use

CF mutation analysis at a greater frequency, at

least initially. The effect of preferential screening of relatives would be to enhance the

efficiency of CF carrier identification. For

example, in a population of 100,000 individuals with 50 percent participation, 75.2 percent

of +/+ couples would be identified. If the

population were relatives of previously identified CF carriers, 50 percent participation identifies 88.3 percent of +/+ couples (7). If the

reproductive behavior were similar, then preferential screening would increase net savings.

On the other hand, if acceptance of CF carrier

screening approaches the 80 percent level that

exists for similar tests, preferential screening of

relatives will have little net economic effect.

Subsequent generations. Future offspring of

+/- couples might preferentially seek CF mutation analysis because their carrier risk will be 1

in 2. In contrast, offspring of -/-couples will

have a very low risk of being carriers and might

be less likelv to utilize CF tests. Such a scenario ./
226 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

would decrease costs of screening and increase

net savings.

SUMMARY AND CONCLUSIONS

One of the least examined of the many issues

surrounding CF carrier screening is the potential

systemwide savings or costs if large numbers of

individuals are screened. Examining costeffectiveness for CF carrier screening, however, is

fraught with technical and social pitfalls. In 1983,

the President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research concluded the fundamental value of

CF carrier screening rests in its potential for

providing people with information they consider

beneficial for autonomous reproductive decisionmaking. In short, personal considerations of having

information-as well as societal considerations of

avoiding eugenics, stigmatization, and discrimination—

outweigh considerations of cost-effectiveness. There

is no intimation in OTA’s analysis that something

that saves or costs money is more or less desirable

from a welfare standpoint. Nevertheless, while a

cost-effectiveness analysis of CF carrier screening is

useful to examine issues of resource allocation,

some will find it offensive that such calculations are

even performed in the context of genetic screening,

since at its core it involves the potential to terminate

affected pregnancies.

Overall, whether CF carrier screening can be paid

for on a population basis through savings accrued by

avoiding CF-related medical and caregiving costs

depends on the assumptions used—including how

many children people will have, average CF medical

costs, and average time and cost devoted to caring

for a child with CF, as well as variations in

reproductive behaviors, costs of CF mutation analyses, and screening participation rates. Eight of 14

scenarios examined result in a net negative output to

the economy over no screening. In the remaining

scenarios, CF carrier screening is cost-effective, but

most of these scenarios involve 100 percent participation, test sensitivity, or selective termin ation—all

unlikely to be realized in the near term, if ever.

Nevertheless, CF carrier screening can save money

compared to no screening even under less absolute

circumstances. The balance between net savings

versus net costs in nearly all scenarios is free. How

many individuals participate in screening is relatively unimportant to cost-effectiveness, but it is

clear the frequency of affected pregnancies terminated and the assay’s price will ultimately affect this

balance.

1.

2.

3.

4,

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

CHAPTER 9 REFERENCES

Ashton, G. C., ‘‘Mismatches in Genetic Markers in a

Large Family Study,” American Journal of Human

Genetics 32:601-613, 1980.

Beaudet, A. L., Howard Hughes Medical Institute,

Houston, TX, remarks at the 8th International Congress of Human Genetics, Washington, DC, October

1991.

Beaudet, A. L., Howard Hughes Medical Institute,

Houston, TX, personal communications, November

1991, February 1992.

Boat, T.F., “Cystic Fibrosis,” Textbook of Respiratory Medicine, J.F. Murray and J.A. Nadel (eds.)

(Philadelphia, PA: W.B. Saunders, 1988).

Boehm, C.D., and Kazazian, H. H., Jr., “Prenatal

Diagnosis by DNA Analysis,” The Unborn Patient:

Prenatal Diagnosis and Treatment, 2nd cd., M.R.

Harrison, M.S. Golbus, and R.A. Filly (MIs.) (Philadelphia, PA: W.B. Saunders Co., 1991).

Botkin, J. R., and Alemagno, S., “Carrier Screening

for Cystic Fibrosis: A Pilot Study of the Attitudes of

Pregnant Women,” American Journal of Public

Health 82;723-725, 1992.

Cox, TK., and Chakravarti, A., ‘ ‘Detection of Cystic

Fibrosis Gene Carriers: Comparison of Two Screening Strategies by Simulations, ’ American Journal of

Human Genetics 49( Supp.):327, 1991.

Cystic Fibrosis Foundation, Cystic Fibrosis Patient

Registry (Bethesda, MD: Cystic Fibrosis Foundation,

1989).

Davis, J. G., New York Hospital, New York, NY,

personal communication, March 1992.

Fenerty, J. P., and Garber, A. M., Costs and Benejlts of

Prenatal Screening for Cystic Fibrosis, Working

Paper No. 2749 (Cambridge, MA: National Bureau

of Economic Research, 1988).

Garber, A. M., and Fenerty, J. P., “Costs and Benefits

of Prenatal Screening for Cystic Fibrosis, ’ Medical

Care 29:473-491, 1991,

Kabac~ M., Zippin, D., Boyd, P., et al., “Attitudes

Toward Prenatal Diagnosis of Cystic Fibrosis Among

Parents of Affected Children, ” Cystic Fibrosis:

Horizons. Proceedings of the 9th International

Cystic Fibrosis Congress, D. Lawson (cd.) (New

York, NY: John Wiley & Sons Inc., 1984).

I.ebo, R. V., Cunningham, G., Simons, M, J., et al.,

“Defining DNA Diagnostic Tests Appropriate or

Standard of Clinical Care,” American Journal of

Human Genetics 47:583-590, 1990.

Lippman, A., “Prenatal Genetic Testing and Screening: Constructing Needs and Reinforcing Inequities, ’ American Journal of Law and Medicine

17:15-50, 1991.
Chapter =osts and Cost-Effectiveness ● 227

15.

16.

17.

18.

19.

20.

21.

22.

23.

24,

25,

Lippman, A., “Mother Matters: A Fresh Imok at

Prenatal Diagnosis and the New Genetic Technologies, ” Reproductive Genetic Testing: Impact on

Women, proceedings of a conference, Nov. 21, 1991.

MacLusky, I., McLaughlin, F. J., and Isvinson, H. R.,

“Cystic Fibrosis: Part l,” Current Problems in

Pediatrics, J.D, Lockhart (cd.) (Chicago, IL: Year

Book Medical Publishers, 1985).

MacIntyre, S., and Sooman, A., ‘ ‘Non-Paternity and

Prenatal Genetic Screening,’ Lancet 338:869-871,

1991.

Miller, S. R., and Schwartz, R. H., ‘‘Attitudes Toward

Genetic Testing of Amish, Mennonite, and Hutterite

Families With Cystic Fibrosis, American lourna[ of

Public Health 82:236-242, 1992.

Mosher, W. D., and Pratt, W. R., “Fecundity and

Infertility in the United States, 1965 -88,” Ad}ance

Data From Vital and Health Statistics, No. 192

(Hyattsville, MD: National Center for Health Statistics, 1990).

Ng, I. S. L., Pace, R., Richard, M. V., et al., “Methods

for Analysis of Multiple Cystic Fibrosis Mutation s,’

Human Genetics 87:613-617, 1991.

Pauly, M. V., “The Economics of Cystic Fibrosis, ”

Textbook qf Cjstic Fibrosis, J.D. Lloyd-Still (cd.)

(Boston, MA: PSG, Inc., 1983].

Pauly, M. V., ‘‘Cost-Effectiveness of Screening for

Cystic Fibrosis, ” contract documents prepared for

the U.S. Congress, Office of Technology Assessment, August 1991, November 1991, February 1992.

Poling, S., Parent, Silver Spring, MD, personal

communication, December 1991.

Population Reference Bureau, 2991 World Population Data Sheet (Washington, DC: Population Reference Bureau, 1991 ).

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Screening and Counseling for Ge26.

27.

28.

29.

30.

31.

32.

33.

34.

netic Conditions: The Ethical, Social, and Legal

Implications of Genetic Screening, Counseling, and

Education Programs (Washington, DC: U.S. Government Printing Office, 1983).

Schulman, J. D., Genetics & IVF Institute, Fairfax,

VA, personal communication, December 1991.

Shoshani, T., Augarten, A., Gazit, E., et al., “Association of a Nonsense Mutation (W1282X), the Most

Common Mutation in Ashkenazi Jewish Cystic

Fibrosis Patients in Israel, With Presentation of

Severe Disease,” American Journal of Human Genetics 50:222-228, 1992.

Singer, E., ‘‘Public Attitudes Towards Genetic Testing,’ Population Research and Policy Re~iew 10:235-

255, 1991.

U.S. Congress, Office of Technology Assessment,

Infertility: Medical and Social Choices, OTA-BA358 (Washington, DC: U.S. Government Printing

Office, 1988).

U.S. Congress, Office of Technology Assessment,

New De~elopments in Biotechnology: Public Perceptions of Biotechnology, OTA-BP-BA-45 (Washington, DC: U.S. Government Printing Office, May

1987).

Wertz, D. C., Janes, S. R., Rosenfield, J. M., et al.,

“Attitudes Toward the Prenatal Diagnosis of Cystic

Fibrosis: Factors in Decision Making Among Affected Families, ” American Journal of Human

Genetics 50:1077-1085, 1992.

Wertz, D, C., Rosenfield, J. M., Janes, S. R., et al.,

“Attitudes Toward Abortion Among Parents of

Children With Cystic Fibrosis,” American Journal

of Public Health 81 :992-996, 1991.

Wilkerson Group, Inc., Annual Cost of Care for

C>stic Fibrosis Patients (New York, NY: Wilkerson

Group, Inc., 1991).

Witt, D., Kaiser Permanence Medical Group, San

Jose, CA, personal communication, March 1992.
Chapter 10

Cystic Fibrosis Carrier Screening in

the United Kingdom
Contents

Page

GENETIC SERVICES IN THE UNTIED KINGDOM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

Cystic Fibrosis in the United Kingdom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

The Role of the Medical Research Council in Cystic Fibrosis Carrier Screening . . . . 232

THE CYSTIC FIBROSIS RESEARCH TRUST PILOT PROGRAMS . . . . . . . . . . . . . . . 233

University Hospital of Wales, Cardiff, Wales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Western General Hospital, Edinburgh, Scotland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

Guy’s Hospital, London, England . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

OTHER PILOT PROGRAMS IN THE UNITED KINGDOM . . . . . . . . . . . . . . . . . . . . . . . 238

St. Mary’s Hospital Medical School, London . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

PROSPECTUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

CHAPTER 10 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242

Boxes

1O-A. The Couples Approach to Carrier Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

1O-B. Cardiff Protocol for Evaluating Psychological Sequelae . . . . . . . . . . . . . . . . . . . . . . . 237

1O-C. Carrier Screening in Denmark . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

Figures

10-1. Plan for Screening and Followup in West Glamorgan, Wales (Individuals) . . . . . . 235

10-2. Plan for Screening in a Cardiff, Wales General Practice (Couples) . . . . . . . . . . . . . 237

10-3. Carrier Screening in Primary Care (St. Mary’s Hospital) . . . . . . . . . . . . . . . . . . . . . . 239

Tables

10-1. Results of the Edinburgh Pilot program (as of December 1991) . . . . . . . . . . . . . . . . 238

10-2. International Cystic Fibrosis Carrier Screening Pilot Programs . . . . . . . . . . . . . . . . . 239

10-3. Members of the European Concerted Action on Cystic Fibrosis

(as of February 1991) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Chapter 10

Cystic Fibrosis Carrier Screening in the United Kingdom

Three pilot projects to explore the implications of

population screening for cystic fibrosis (CF) carriers

are under way in the United Kingdom, funded by the

Cystic Fibrosis Research Trust (CF Trust), a private,

nonprofit philanthropic organization. The goals of

the programs, which began in 1990, are to identify

the most appropriate populations for screening,

evaluate various test protocols and techniques, arid

understand the psychosocial consequences of carrier

identification. In addition to pilot programs supported by the CF Trust, at least two other ongoing CF

carrier screening pilots are supported by private and

various research funds.

This chapter discusses the structure of CF carrier

screening programs in the United Kingdom-the

most extensive, comprehensive, and advanced pilots

currently under way. It analyzes the strategies being

used and reports on results recorded to date—both of

which could bear on how CF carrier screening is

approached in the United States, This chapter is

based, in part, on interviews conducted by OTA

during June 1991 visits with pilot project staff and

staff of the Medical Research Council (MRC).

GENETIC SERVICES IN THE

UNITED KINGDOM

Through the British National Health Service

(NHS), all citizens receive medical care. Individuals

self-assign themselves to a general practitioner (GP)

within close geographic proximity. Private, for-pay

medical care is also available to those willing and

able to pay. Through the NHS, the British government informs GPs of new tests and medical practices, although some believe that such information

does not always get communicated in a timely

fashion (12). AS in the United States, GPs are likely

to learn about new developments in diagnosis and

therapy through continuing education.

The British health care and legal systems have

protected medical professionals from malpractice

suits because there is no contingency fee arrangement as in the United States. Moreover, in general,

patients can only sue for actual cost. Because health

care is free, the actual costs are likely to be low.

In the United Kingdom, individuals are usually

referred to a genetics unit by their GP, who is

responsible for primary health care screening and

prevention and is the usual means by which individuals are introduced to the need for genetic information. Family plarming and prenatal clinics are also

sources of genetics information. Ideally, when a

woman tests positive for pregnancy, she is booked

with a hospital prenatal clinic for management of her

pregnancy, where she may receive relevant genetic

information. The provision of routine genetic counseling is increasingly offered through primary care.

Unusual or difficult cases are referred to a genetics

specialty unit.

Medical genetics is a rapidly developing specialty

that has been widely introduced in the United

Kingdom. Population screening and prenatal diagnosis have been available for groups at risk for

Tay-Sachs disease and thalassemias. Genetics services routinely deliver neonatal screening for phenylketonuria and congenital hypothyroidism, maternal serum alpha-fetoprotein screening, and fetal

karyotyping in women of advanced maternal age

(12,18). A national network of regional genetic

services exists but is currently threatened by recent

governmental changes in the NHS (2,10,12).

Cystic Fibrosis in the United Kingdom

In Great Britain, about 300 babies a year are born

with CF. The average annual cost of treating

someone with CF is estimated to be £5,000 (20) to

f 10,000 (6). The Caucasian population in South East

England has undergone extensive genetic analysis

for CF carrier status (8,9), and the frequency of the

DF508 mutation in this part of England has been

variously reported at a minimum of 70 percent in

adult CF populations (21),71.5 percent (8,9), and 80

percent (27). In the Scottish population, DF508

represents about 71 percent of all CF mutations

(15,22). (See app. A for international distribution of

mutation frequencies.)

Buccal mouthwashes are increasingly used as the

source of DNA for screening in the United Kingdom.

The mouthwash technique is inexpensive and considered safe, and the DNA can be extracted rapidly

and reliably in sufficient quantity for amplification

by polymerase chain reaction (PCR; ch. 4). Welsh

investigators have compared mouthwash, bucca1

scrapes, and finger pricks as the methods for sample

–23 l–
232 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

collection, and determined that the mouthwash is the

most desirable in terms of patient acceptability,

successful DNA extraction, and cost (12). Among

pregnant women, blood-already being drawn for

other diagnostic tests—is used rather than mouthwash.

With births numbering 700,000 annually, an

estimated 1.4 million screening assays would have

to be performed if all couples were screened

prenatally. About 56,000 carriers would be detected

from this cohort, requiring counseling and the option

of prenatal diagnosis. The identification of 56,000

carriers annually would overwhelm the 157 full-time

doctors and clinical coworkers in clinical genetics

centers in the United Kingdom, excluding laboratory

scientists (10). One survey of health professionals

showed that approximately 75 percent of both GPs

and family planning clinic staff thought that the

introduction of CF carrier screening was appropriate; less than 10 percent opposed it (27).

In addition to staffing difficulties, it is widely

acknowledged in Britain (as it is in the United

States) that there are serious deficiencies in the

teaching of clinical genetics in medical schools,

which makes experts reluctant to rely on primary

care doctors to provide genetics advice (13). In

contrast to the United States, genetic counseling in

Britain is most frequently offered by M.D. and Ph.D.

clinicians. Counselors trained at the level of a

master’s degree are rare; nurses trained in genetics

are more common. As a result, genetic services tend

to be provided through highly specialized, highly

trained individuals. A survey of health visitors (the

U.K. equivalent of a U.S. visiting nurse) showed that

while generic health visitors (i.e., those not working

in genetics) had a reasonable knowledge of the more

obvious aspects of genetic services, there were a

number of areas about which they were unsure.

Furthermore, they viewed their own knowledge of

genetics as poor (7).

The Role of the Medical Research Council in

Cystic Fibrosis Carrier Screening

The MRC is a public agency of the British

Government. “The MRC has a long history of

supporting research of direct relevance to health

services, in addition to, and often built around, the

biomedical and clinical research that forms the bulk

of its work’ (16). Much of the MRC’s health

services research is conducted by its units (comparable to the intramural programs of the U.S. National

Institutes of Health). In 1981, the MRC established

a Health Services Research Panel (HSRP) as an

advisory body to the Council’s Boards and Grants

Committees. In 1986, the HSRP was reconstituted as

a committee, the Health Services Research Committee (HSRC), with powers to promote the development of health services research and to make funding

recommendations (16). In general, HSRC concentrates on: research into the effectiveness and efficiency of health services in implementing medical

knowledge to improve health; and needs for which

effective medical interventions exist or could be

developed in the future. Design and delivery of

health services is integral to the research interests of

the HSRC; thus CF carrier screening projects fall

squarely within its domain (24).

Involvement of the MRC with CF began in 1989

when it received outline proposals for CF carrier

screening pilot studies. At the same time, the CF

Trust invited applications for pilot studies. The

outlines and the proposals funded by the CF Trust

had a broad focus, whereas the MRC was interested

in studies that would address the costs, benefits,

disbenefits, and acceptability of screening programs.

The MRC, therefore, convened a workshop for

geneticists and social scientists to discuss the

research questions raised by CF carrier screening

(24). After the workshop, pilot proposals were

considered. Based on the conclusions of the workshop, the MRC placed a high priority on studies to:

●

●

●

●

●

●

●

evaluate the objectives of screening programs

(e.g., identify carriers to reduce birth incidence,

aid reproductive choice, or provide information);

address the acceptability and participation rate

of carrier screening for different target groups

and in different settings;

compare screened and nonscreened groups;

clarify what information should be provided

about carrier screening to the general public

and to individuals or couples to whom screening might be offered, and evaluate ways of

presenting that information;

assess anxiety specific to carrier screening in

addition to general anxiety levels;

measure short- and long-term outcomes of

carrier status identification;

follow up couples at low risk who subsequently

produce an affected child; and
Chapter 10-Cystic Fibrosis Carrier Sceening in the United Kingdom . 233

● measure the costs of providing a screening

program (17).

In addition to the preceding research issues, the

MRC considers the cost-effectiveness of screening

programs an important factor and encourages researchers to address this issue (24). This could prove

difficult: Because of the way the NHS operates, cost

accounting has always been elusive. Few providers

of genetic services would likely document evidence

of beneficial outcome, workload, or costs for each of

the districts they serve and would have difficulty

assigning a figure to the cost of tests.

The MRC currently supports two projects. A pilot

study at St, Mary’s Hospital Medical School will

produce a videotape for CF carriers and monitor and

evaluate the use of the videotape (£19,000). An

evaluation of carrier screening for CF in couples at

the Human Genetics Unit in Edinburgh also receives

MRC funds (£97,000) (3,24). Some staff working on

the pilot projects finded by the CF Trust also receive

money through the ‘‘Genetic Approach to Human

Health” project. Through this project, the MRC

aims to encourage more applications for studies of

the health services research issues associated with

carrier screening.

THE CYSTIC FIBROSIS

RESEARCH TRUST PILOT

PROGRAMS

The CF Trust, analogous to the Cystic Fibrosis

Foundation in the United States, funds research

related to improved diagnosis, understanding, and

treatment of the disorder. The CF Trust has been the

lead organization in the United Kingdom’s investigation of carrier screening programs. Acknowledging the complexity of a national screening program,

the CF Trust sought advice from an expert panel, the

MRC, and the Department of Health before deciding

to fund three pilot projects for evaluation of heterozy -

gote screening. The three sites to receive funds were:

● University of Wales College of Medicine,

Cardiff, Wales, for 3 years, f 197,540;

. University of Edinburgh, Western General

Hospital, Edinburgh, Scotland, for 3 years,

£197,540; and

. Guys Hospital, London, England, for 2 years,

f 177,775.

In addition to performing their own tests, all three

pilots are simultaneously using Cellmark DiagnosPhoto credit: Peter Harper, University of Wales College of Medicine

Institute of Medical Genetics, University of Wales

College of Medicine, Cardiff, Wales.

tics’ amplification refractory mutation system

(ARMS) multiplex kit. The ARMS multiplex assays

DF508, 621+1 G---›T, G551D, and G542X, with a

sensitivity of 83 percent. Cellmark is not yet

charging for the use of the kits because it has not yet

been licensed to do so.

University Hospital of Wales, Cardiff, Wales

The 3-year pilot project under way at the Institute

of Medical Genetics, University Hospital of Wales

in Cardiff has the following aims:

●

●

●

●

●

evaluate the attitudes of GPs and primary care

staff to CF carrier screening;

evaluate the feasibility of screening for CF

carriers in general practices;

evaluate clients’ interest in and reactions to CF

carrier screening;

develop accurate, informative, and acceptable

educational material for the public and health

professionals; and

consider the possibility of a pilot prenatal

carrier screening project.

In addition to these clinical objectives, the Cardiff

group has established an effective PCR multiplex

system to test for the major CF mutations. The

Institute of Medical Genetics of the University

Hospital of Wales is not a basic CF research group,

but a comprehensive genetics center. As a result, the

clinic assumes the need for well-prepared GPs in

order to make new screening programs work (1 1).

Much of the first year of this pilot was spent

evaluating attitudes about screening in urban and

rural/industrial mining-town general practices. Al-
234 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

though geneticists view CF as a relatively common

genetic disorder, GPs do not; the Cardiff pilot group

did not want to mistakenly assume that GPs would

give the necessary time to ensure a successful

screening program. In addition, the pilot coordinator

has been working with health professionals such as

nurses and midwives to educate them about CF

carrier screening and prepare them for questions that

may arise.

Opportunistic screening refers to the practice of

approaching individuals either in person or via

brochure while they are waiting for appointments for

other reasons at either their GP or family planning

clinic. Screening is offered opportunistically to all

individual adults between the ages of 16 and 45 who

are registered with two general practices in Wales

(each approximately 1,500 individuals). The Welsh

plan for screening and followup of individuals is

depicted in figure 10-1.

Prenatal screening is not offered at this time, but

will be offered in 1993, the third year of the pilot.

Known CF families have been contacted, and family

testing has been completed for that group. Screening

of couples is under consideration (box 1O-A). This

project, if implemented, will offer CF carrier screening to all couples (but not individuals) in a separate

general practice (approximately 1,000 individuals)

who are in the reproductive age group and are

planning a pregnancy (figure 10-2). The attitudes of

participating couples will be evaluated. This protocol, as with all protocols, must be approved by the

Ethical Committee of the Division of Child Health

of the University Hospital of Wales.

Mouthwashes are used for collection of DNA. The

Cardiff multiplex tests for DF508, DI507, G551D,

R553X, and 621+1 G---›T, providing 81.5 percent

sensitivity. As with the other two pilots, Cellmark’s

ARMS is run concurrently, with a sensitivity of 83

percent.

The project is designed to compare the differences

of participation in screening following invitation by

letter, opportunistic invitation, and self-referred

requests for screening. In addition, socioeconomic

variables will be compared, including social class,

age, sex, and marital status. As with the London and

Edinburgh pilots, the Cardiff pilot will also evaluate

the psychological sequelae to screening for CF.

Participants will be asked to complete questionnaires at a minimum of three junctures: prior to

screening, after being told of their carrier status, and

at a 3-month followup. The questionnaires will

evaluate perceived health through the perceived

health measure (14), a shortened State of Anxiety

Inventory (23), a reproductive intentions questionnaire, and a knowledge-of-CF questionnaire. Box

1O-B describes the protocol.

Those who choose not to be screened will be

contacted to determine their reasons for refusing

screening. Finally, the Cardiff team will calculate

the costs and time implications of screening for

general practices and laboratory staff.

Western General Hospital,

Edinburgh, Scotland

The CF pilot at Western General Hospital in

Edinburgh, Scotland is modeled after existing ßthalassemia and Tay-Sachs programs offered

through prenatal clinics in the United Kingdom. The

long-term goal is to introduce prepregnancy CF

carrier screening. The philosophy of this pilot is

markedly different from that of the other two CF

Trust pilots and the program at St. Mary’s Hospital

in London. The pilot director believes that CF

mutation analysis should first be offered to individuals with the most limited choices (i.e., women who

are pregnant) while simultaneously initiating screening in the broader preconception population (3). This

philosophy is based on the assumption that pregnant

couples coming through prenatal clinics are more

motivated, more in need of this type of information,

and more likely to make immediate use of the

information provided through screening (4).

Photo credit: David J.H. Brock, University of Edinburgh

CF mutation analysis of samples in a laboratory at Western

General Hospital, University of Edinburgh, Edinburgh,

Scotland.
Figure 10-1—Plan for Screening and Followup in West Glamorgan, Wales (Individuals)

I ,

1 I ,

Screening invitation letter and recruiting

leaflet (to both sexes in 16-45 age group) Opportunistic invitation

, L

I w

I

. .

,

r I

Questionnaire to a

sample of the group

to assess reasons

for refusal

I 1

I

I Appointment for 1

Negative result

Letter sent explaining

the results. Approximate

residual risk of

being a carrier is

1 in 150.
236 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Box 10-A—The Couples Approach to Carrier Screening

One approach currently used in London and under consideration elsewhere in the United Kingdom is the

‘‘couples’ protocol for carrier screening. This protocol aims to identify high risk couples (both partners are carriers,

thereby each pregnancy has a 1 in 4 risk of having an affected child). Using this protocol, couples are screened as

a unit and receive their results as either high or low risk of producing an affected child Individual carrier status is

not discussed Even if the geneticist determines that one of the members of the couple is a carrier (a +/- couple),

that couple is grouped with negative-screening couples (-/-) in terms of risk. (See figure 10-2 for protocol.)

Several medical geneticists in the United Kingdom are disturbed by this approach as it involves a failure to

disclose known information. At a meeting convened by the Medical Research Council in May 1991, participants

considered the concept of blind testing. If test results could not be attributed to an individual but rather the couple,

then, the group concluded information was not being concealed and the protocol could be considered ethically

acceptable.

Approximately 3 percent of couples will test +/-, and their risk of producing an affected child is 1 in 600. This

compares to the lower risk group of -/- couples, whose chances of producing an affected child are 1 in 50,000. The

residual risk to the first group presents ethical dilemmas currently being sorted out in the United Kingdom.

Proponents of this approach feel it is more economical and reduces the anxiety associated with knowing one’s

carrier status. In addition, both partners are screened simultaneously. If the woman is pregnant, the amount of time

needed to identify a couple at risk is reduced.

Just how to obtain informed consent in this process remains a problem, although proponents claim that if the

contractual agreement is to identify only high risk couples, then those who find such an approach disturbing could

opt out. In addition, the implications for liability should a couple deemed ‘low risk’ give birth to a child with cystic

fibrosis have not been addressed.

SOURCE: Office of Technology Assessment, 1992.

When a woman is booked for her frost appoint- and G542X, providing a predictive value of 85

ment through a family planning service, she also percent in the population) and then testing her

receives a CF carrier screening ‘booklet. Upon her

arrival at the clinic, a genetic nurse or midwife (who

has been previously trained to handle CF questions)

asks her if she wants to be screened. Women who are

late in their pregnancy (beyond 16 weeks’ gestation)

are excluded, as are those with no partners, since

prenatal screening is most informative using results

from both parents, The goal of the program is to

reach at least 80 percent of patients coming through

a major maternity hospital with the aim to expand to

two other hospitals in the near future. In addition to

the prenatal program, the Edinburgh pilot study is

going back to CF families and offering the test.

Offering screening to school-age individuals has

been explored but not initiated. In a study of 14- to

16-year-old school children in Edinburgh, investigators found a positive attitude to carrier screening for

CF and to the offer of prenatal tests of those couples

shown both to be carriers (5).

The Edinburgh pilot employs a two-step model,

first screening the pregnant woman for carrier status

using assays for three mutations (DF508, G551D,

partner for 15 mutations if she is diagnosed as a

carrier (evaluating 12 more mutations provides a

predictive value of 92 percent in the population).

The Edinburgh laboratory is currently running 50 to

60 samples a week and running the ARMS test kit

simultaneously. By December 1991, more than

2,000 samples had been run, detecting 74 carriers

(table 10-1).

Like the other pilot programs, Edinburgh is

devoting considerable effort to examining the acceptability of offering the test, in this case prenatally. Maternal and parental anxiety is the focus of

the assessments—in specific, determining to what

extent offering the test to pregnant women raises

anxiety in preconception and prenatal populations.

Consulting psychologists and psychiatrists are developing a survey instrument that will measure

anxiety, self-esteem, and perceptions of stigma in

those screened.

As noted earlier, the program received funds in

January 1992 from the MRC to carry out a separate
Chapter IO--Cystic Fibrosis Carrier Sceening in the United Kindom . 237

Figure 10-2—Plan for Screening in a Cardiff, Wales General Practice (Couples)

I I

I Consent form I

Sample collection (mouthwash)

Both partners positive

Told of a high risk

Offered specialist

genetic counseling

Both partners negative

Told of a low risk

I

SOURCE: P. Harper, University of Wales College of Medicine, Cardiff, Wales, personal communication, 1991.

Box 10-B---Cardiff Protocol for Evaluating Psychological Sequelae

Step I

Participants are invited either through the mail or directly through their general practitioner. Prior to screening they

are asked to complete the perceived health measure questionnaire and the State of Anxiety Inventory. Immediately

prior to counseling, they are asked to complete the reproductive intentions questionnaire and the knowledge-of-CF

questionnaire.

Step 2

Within 1 week of notification of their carrier status, all participants are asked to complete the questiomaires again.

Step 3

Three months after screening, participants are again sent all the questionnaires.

SOURCE: P. Harper, Institute of Medical Genetics, University Hospital of Wales, Cadiff, personal communication 1991.
238 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table 10-1—Results of the Edinburgh Pilot Program

(as of December 1991)

Number of women approached. . . . .

Ineligible for screening

late gestation. . . . . . . . . . . . . . . . . .

abnormal pregnancy. . . . . . . . . . . .

no partner. . . . . . . . . . . . . . . . . . . . .

other. . . . . . . . . . . . . . . . . . . . . . . . .

Total. . . . . . . . . . . . . . . . . . . . . . . .

Eligible for screening. . . . . . . . . . . . . .

Declined screening. . . . . . . . . . . . . . .

Screened. . . . . . . . . . . . . . . . . . . . . . .

Carrier women. . . . . . . . . . . . . . . . . . .

Carrier partners. . . . . . . . . . . . . . . . . .

Carrier frequency found. . . . . . . . . . .

Carder frequency expected. . . . . . . .

2,780

245

50

31

35

361 (13 percent)

2,419 (87 percent)

331 (12 percent)

2,088 (75 percent of all;

86 percent of eligible)

74

3

1 in 28

1 in 30

SOURCE: D.J.H. Brock, Western General Hospital, Edinburgh, Scotland,

personal communication, 1991.

trial of couples screening in another maternity

hospital in Scotland.

Guy’s Hospital, London, England

Guy’s Hospital in London offers CF carrier

screening to adults of reproductive age (18 to 45

years old) through a general practice. Screening

prenatally is not the goal of the program. The

philosophy of this pilot is to introduce screening

through the GP so that after the pilot programs

expire, screening can be run by the GPs.

The predictive value of the test when used in the

Guy’s population is approximately 80 percent using

the four mutations detected with the Cellmark

ARMS kit. Through mid-1991, approximately 200

samples had been run at a rate of 10 to 20 per week

(l).

As with the Cardiff and Edinburgh pilot programs, participants are asked to complete the psychological questiomaires (which were developed in

collaboration with a Guy’s psychologist). At the end

of the pilot programs, all three groups will compare

results.

OTHER PILOT PROGRAMS I N

THE UNITED KINGDO M

In addition to the pilot programs funded by the CF

Trust, two other programs-funded privately or by

a variety of public and private funding mechanisms—

have also begun to evaluate the implications of

population carrier screening for CF. The most active

non-CF-Trust program in the United Kingdom is at

Box 10-C-Carrier Screening in Denmark

The carrier frequency for the DF508 mutation is

nearly 88 percent in Denmark. This makes screening simpler because of the higher sensitivity of the

test. This factor, combined with a national health

program, made the introduction of CF carrier

screening more feasible. Using national health

service funds, carrier screening is offered to all

pregnant women seen at an out patient clinic at the

Rigshospitalet in Copenhagen, as well as to families

of CF patients. Blood samples are drawn and tested

for the presence of the DF508 mutation. Among

3,664 women tested as of September 1991,91 were

found to be carriers of the DF508 mutation (1 in 40).

When the partners of these women were tested, only

one was found to also be a carrier of the DF508

mutation. Prenatal diagnosis revealed that the fetus

was homozygous for DF508 and the pregnancy was

terminated. In addition, prenatal diagnosis was

performed on an additional 42 fetuses. Of these, 24

were found to be carriers (heterozygotes) for the

DF508 mutation.

SOURCE: M. Schwartz and N.J. Brandt, Rigshospitale, Copenhagen,. Denmark personal communication, 1991.

St. Mary’s Hospital Medical School, Imperial College, London. The St. Mary’s program is similar to

those in Cardiff and at Guy’s Hospital, focusing on

screening nonpregnant adults of reproductive age.

Another program, funded entirely through private

sources, is at St. Bartholomew’s Hospital (Bart’s) in

London. The Bart’s program is unique, in that it

offers only couples screening. In fact, the director of

the Bart’s program has been the most outspoken

advocate in the United Kingdom of the couples

screening approach (box 1O-A) (4). Pilots are also

under way in Italy, Denmark (box 1O-C), and Austria

(table 10-2).

St. Mary’s Hospital Medical School, London

The pilot study operated out of St. Mary’s

Hospital Medical School in London is evaluating

preconception CF carrier screening of males and

females of reproductive age through three GPs and

three family planning clinics (figure 10-3). This

genetic service opted to offer the test to nonpregnant

individuals of reproductive age, because the director

believes screening this population maximizes reproductive choice and autonomy.
Chapter 10-Cystic Fibrosis Carrier Sceening in the United Kingdom . 239

Table 10-2—lnternational Cystic Fibrosis Carrier

Screening Pilot Programs

Country institution Target population

Austria University of Vienna

Denmark Rigshospitalet

England St. Mary’s

Guy’s

St. Bartholomew’s

Italy University of Padua

Wales University of Wales

College of Medicine

Scotland University of Edinburgh

Newborns

Prenatal

Adult preconception

Adult preconception

Adult preconception

Newborns

Adult preconception

Prenatal

SOURCE: Office of Technology Assessment, 1992.

Using mouthwash samples, the St. Mary’s group

is presently looking for the DF508, G551D, and

R553X mutations, which together should detect 82

percent of the CF carriers in their population.

Through mid-1991, St. Mary’s had screened about

1,600 individuals at the rate of approximately 50

samples a week. Rough estimates of the cost of

screening run about £1.75 per sample for laboratory

costs alone. Estimating total costs, however, is

difficult as some laboratory staff are paid out of a

research grant, and others are paid through the NHS.

Figure 10-3—Carrier Screening in Primary Care

(St. Mary’s Hospital)

Information

(Target population: males and females, 16-44 years)

Negative result

(Informed by letter; 1 in 130 risk)

Positive result (820/. of carriers identified)

Counseling

Test other relatives

Negative result

(Informed by letter;

test partner for additional mutations)

SOURCE: R. Williamson, St. Mary’s Hospital, London, England, personal

communication, 1991.

Counseling is not a major cost as it is, for the most

part, carried out by GPs or practice nurses who are

already employed by the NHS (28). Because the

tests are part of a research protocol, for which the

laboratory does not charge, they do not pay PCR

royalties.

One approach used by this group is opportunistic

screening. The St. Mary’s group has found that

approximately 66 percent of individuals approached

through their GP eventually request screening, while

87 percent of individuals in the family planning

clinics request the test (25,28). Another approach

being tested by this pilot group involves solicitation

by invitation letter. Individuals receive a letter

offering the test on Saturday mornings at their GP’s

office. The response rate of this method approximates 10 percent (25).

With both approaches, each person is given a

leaflet that explains the test. Those who opt for

screening are told about the limited sensitivity of the

assay. The results are sent through the mail. The

letter to those screening negative reemphasizes the

sensitivity of the test, informs the individual that his

or her risk of being a carrier has been reduced to 1 in

130, and offers screening for partners or spouses.

Carriers are invited to attend a counseling session

where risks are explained and the testing of partners

or relatives is discussed. The partners of identified

carriers are screened for several additional mutations, which brings the detection rate up to around 86

percent (26,29).

Participants in this screening program were asked

how they thought their future reproductive plans

might be affected if both they and their partners were

found to be carriers. For those with no experience

with CF, 38 percent felt they might choose not to

have children, 78 percent would request prenatal

diagnosis should they become pregnant, and 16

percent would not consider terminating an affected

pregnancy. For those who had a relative or knew

someone with CF, 45 percent felt they might choose

not to have children, 82 percent would opt for

prenatal diagnosis in pregnancy, and 20 percent

would not consider terminating an affected pregnancy (25).

This study has also begun offering screening at

selected work sites, such as police barracks or the

Royal Mail, There are also plans to mail the

mouthwash kits to the homes of relatives of carriers.
240 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

I

I

I

PROSPECTUS

The future of broad population carrier screening

for CF in the United Kingdom is yet to be decided.

Many interviewees were skeptical that widescale

screening will be pursued by the NHS once the pilot

programs are completed. Moreover, even if the NHS

takes up carrier screening, there is no guarantee that

it would last. It is generally easier to retract programs

in the United Kingdom than in the United States.

As in the United States, there is speculation about

whether the necessary infrastructure exists to proceed with broad based screening. In the United

Kingdom, it will be necessary to provide:

●

●

●

information to the population;

a system for collecting samples from a cohort of

the population at some point before reproduction, and delivering the samples to the laboratory;

a network of diagnostic laboratories with a

quality control system;

●

●

●

●

●

a system for reporting the results to doctors and

the people concerned;

an information storage and retrieval system;

information and counseling for carriers;

adequate expert centers for counseling couples

at risk and providing prenatal diagnosis; and

a system for monitoring the service (18).

There is a general consensus in the United

Kingdom that newborn screening would be an

inefficient approach to reducing the incidence of CF.

One of four carrier couples would already have an

affected child before being identfied as carriers, and

an additional 25 percent would not be identified

because their child had inherited neither CF mutation. Ensuring that this information follows the

carrier child into adulthood is also problematic (27).

Legal, ethical, and logistical problems also make

school-based screening programs difficult to implement in the United Kingdom (4).

There remains some disagreement as to whether

prenatal CF carrier screening unduly raises maternal
Chapter IO-Cystic Fibrosis Carrier Sceening in the United Kingdom . 241

anxiety in the approximately 24 of 25 women who

will test negative. Proponents of prenatal screening

feel that pregnant couples are most in need of and

most likely to use this information. Furthermore, the

infrastructure already exists for working with these

individuals. Those opposed to prenatal screening

feel that it raises anxiety at an already anxious time

and leaves little time for reflection (18,27). People of

this view tend to believe that screening should be

offered preconceptionally, when carrier couples will

have a maximum range of reproductive options.

Carrier screening offered when pregnancy is known

has the advantage of a captive population, but the

disadvantage of limited time for screening and

decisionmaking, as well as eliminating the option of

avoiding conception if both partners are carriers.

The pilot studies will help clarify some of these

issues as they encompass both prenatal and preconception populations.

If the pilots are successful and the NHS embraces

the notion of a widescale screening program, the

laboratory service would be provided by centralized

regional DNA laboratories run by the NHS. One area

in which the United Kingdom lags behind the United

States is in the area of quality control and assurance.

Lacking regulatory agencies comparable to the U.S.

Health Care Financing Administration and the U.S.

Food and Drug Administration, laboratories need

only voluntarily comply with quality standards.

In the late 1980s, the European Concerted Action

on Cystic Fibrosis was formed for the purposes of

data coordination, information exchange, and establishment of international standards of quality control

(table 10-3). Organized out of St. Mary’s Medical

School in London, the consortium supplies every

participating laboratory with oligonucleotides for

CF analysis in exchange for data. The group

interacts with the Genetic Analysis Consortium in

North America, but does not consider itself a

‘‘ Euro-equivalent,’ in that it is not primarily a

research group, but a clinical assistance group. A

newsletter published six times a year serves as a

point of exchange for information about ongoing

work and technical advances.

Coded samples and a list of mutations to be tested

were distributed in June 1991 to 35 voluntary

hospital-based research groups. A database program

for the collection of mutation and patient data is

available through the European Concerted Action on

Cystic Fibrosis (19). The program will allow laboraTable 10-3—Members of the European

Concerted Action on Cystic Fibrosis

(as of February 1991)

Australia

Austria

Belgium

Bulgaria

Cuba

Czechoslovakia (former)

Denmark

England

Finland

France

Germany

Greece

Israel

Italy

The Netherlands

New Zealand

Northern Ireland

Norway

Poland

Portugal

Republic of Ireland

Scotland

South Africa

Spain

Sweden

Switzerland

USSR (former)

Wales

Yugoslavia (former)

SOURCE: R. Williamson, St. Mary’s Hospital Medical School, London,

England, personal communication, 1991.

tories to computerize their records and analyze data

according to mutations, clinical details, and ethnic

groups. Each of the pilot projects is participating in

this quality control exercise. The MRC is seeking

additional information regarding quality control and

assurance.

Establishing the infrastructure necessary for CF

carrier screening, if it is done, could lay the ground

work for other forms of genetic screening in the

future. Current reform of the NHS might well be the

best predictor of the future of genetic screening

programs in the United Kingdom. Under the new

reforms, health authorities will assess the health

needs of their resident populations and then negotiate contracts to purchase the services that they

expect will achieve the most improvements in health

(10). With the reforms, hospitals can function

outside health authority control as ‘‘self-governing

hospital trusts,’ and it is not yet clear how specialized, preventive, genetic services will be administered under this new plan. They may be deemed too

costly. Results of the pilot programs in the United

Kingdom will provide valuable information on the

ability of primary care providers to assist in screening, the acceptability by the public of screening, and

the most appropriate population for screening.

SUMMARY AND CONCLUSIONS

The private CF Trust is largely responsible for the

existence of CF carrier screening pilot projects in the

United Kingdom. Were the availability of government funding the determinant of pilot project

initiation, it is uncertain any pilots would exist.

Results of pilot studies in the United Kingdom will
242 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

be directly relevant to consideration of population

screening in the United States because of similar

concerns about the appropriate target population,

levels of anxiety, and the role of primary care

providers. Although the latter concern is of a

different nature in the United Kingdom because of

the role of the general practitioner and the National

Health Service retain, the ability of GPs to participate in screening in the United Kingdom will be of

significant interest in the United States.

The role of the British GP as the likely first point

of contact for CF carrier screening makes preconceptional carrier screening of adults more easily achieved

than in the United States, where primary care

physicians are less likely to refer individuals for

screening in the absence of a positive family history.

Targeting GPs as important collaborators and resources in CF carrier screening is done by nearly

every British pilot program. GPs are actively recruited to participate in the development and implementation of screening.

Prenatal clinics provide another population easily

targeted for screening. Yet there is no consensus on

the appropriateness of targeting pregnant women for

CF carrier screening. Only the Edinburgh pilot

project is actively recruiting pregnant women. Concerns about raising anxiety in pregnant women and

the logistical restrictions to offering first, rather than

second, trimester prenatal diagnosis, are the impetus

for screening programs airned at preconceptional

individuals. Anxiety levels are being followed by

the CF Trust pilot projects and the results of these

analyses should shed light on the validity of those

concerns.

Debate over couples screening has focused on the

ethics of not informing carriers of their status in

couples in which one partner is a CF carrier and the

other has a negative test result (an informing practice

that would be considered legally and ethically

dangerous in the United States). In addition, those

opposed to the concept of couples screening fmd the

treatment of individuals as reproductive units unsettling, given the possibility of nonpaternity or new

partners in the future. Unlike the United States, the

British medical community does not operate under

the fear of malpractice or litigation. Because the

British pay for their health care indirectly, through

taxation, they do not view themselves as consumers

or buyers of services.

While screening cost is a major consideration in

the United States, it is viewed differently in the

United Kingdom, as the total cost is likely to be

borne by the NHS. New programs, such as routine

CF carrier screening, must compete with other

desirable projects for available funds. In addition,

services are more centralized, lowering overall

costs. Reform of the NHS, however, will likely alter

the manner in which genetic services are offered and

made available.

Except for samples from pregnant women, investigators in the United Kingdom rely on mouthwash

for their DNA extractions. This approach, seldom

used in the United States, is thought to be as

effective for DNA extraction as other sources and is

less costly. In addition, investigators feel that the use

of this noninvasive procedure contributes to higher

rates of participation in screening programs. Quality

control and assurance, currently conducted on an

informal basis throughout the United Kingdom,

would have to be addressed.

The British health care system is significantly

different from that found in the United States. The

existence of preliminary carrier screening pilot

projects in no way commits the system to sustain the

programs. It is generally easier in the United

Kingdom than in the United States to retract policies

or cease offering services if they are deemed

unnecessary or inappropriate. Results of the pilot

programs in the United Kingdom will provide

valuable information on the ability of primary care

providers to assist in screening, the acceptability of

screening by the public, and the most appropriate

population for genetic carrier screening.

CHAPTER 10 REFERENCES

1.

2.

3.

4.

5.

Bobrow, M., Guy’s Hospital, Imndon, personal

communication, June 1991.

Brock, D.J.H., ‘‘A Consortium Approach to Molecular Genetic Se~ices,” Journal of Medical Genetics

27:8-13, 1990.

Brock, D. J. H., University of Edinburgh, Western

General Hospital, Edinburgh, Scotkmd, personal

communications, June 1991, December 1991.

Brock, D.J.H., Memie, M. E., McIntosh, I., et al.,

‘‘Heterozygote Screening for Cystic Fibrosis,’ Antenatal Diagnosis of Fetal Abnormalities, J.O. Drife

and D. Donnai (eds.) (London, England: SpringerVerlag, 1991).

Cobb, E., Holloway, S., Elton, R., et al., “What Do

Young People Think About Screening for Cystic
Chapter IO--Cystic Fibrosis Carrier Sceening in the United Kingdom ● 243

6.

7.

8.

9.

10.

11.

1~.

13.

14.

15.

16.

17.

Fibrosis?, ’ Journal of Medical Genetics 28;322-

324, 1991.

Dodge, J. A., ‘‘Implications of the New Genetics for

Screening for Cystic Fibrosis,’ Lancet 2(8612):672-

674, 1988.

Guilbert, P., and Cheater, F., “Health Visitor’s

Awareness and Perception of Clinical Genetic Services, Journal of Medical Genetics 27:508-511,

1990.

Harris, A., “DNA Markers Near the Cystic Fibrosis

Lmcus: Further Analysis of the British Population,”

Journal of Medical Genetics 27:39=$1, 1990.

Harris, A., Beards, F., and Mathew, C., “Mutation

Analysis at the Cystic Fibrosis Imcus in the British

Population, ’ Human Genetics 85:408-409, 1990.

Harris, R., “Genetic Services in Britain: A Strategy

for Success After tie National Health Service a n d

Community Care Act 1990,” Journal of Medical

Genetics 27:71 1-714, 1990.

Harper, P., “Genetic Services in the Community,”

Journal of Medical Genetics 27:473-474, 1990.

Harper, P., Institute of Medical Genetics, University

of Wales College of Medicine, Cardiff, Wales,

personal communications, June 1991, December

1991.

Johnston, A. W., “Teaching of Clinical Genetics in

Britain: A Report From the Royal College of

Physicians of hndon,’ Journal of Medical Genetics

27:707-709, 1990.

Marteau, TM., Johnston, M., Shaw, R. W., et al.,

“The Impact of Prenatal Screening and Diagnostic

Testing Upon the Cognition, Emotions, and Behaviour of Pregnant Women, Journal of Psychosomatic

Research 33:7-16, 1989.

McIntosh, I., Curtis, A., hrenzo, M-L., et al., “The

Haplotype Distribution of the AF508 Mutations in

Cystic Fibrosis Families in Scotland,” Human Genetics 85:419420, 1990.

Medical Research Council, Health Services Research, brochure available from the MRC, Park

Crescent, I.mndon, England.

Medical Research Council, Report on the HSRC

Workshop to Discuss Research in Cystic Fibrosis

Carrier Screening (91/HSRC 163, file No. A861/

132), 1991.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

Modell, B., ‘‘Cystic Fibrosis Screening and Community Genetics, “ Journal of Medical Genetics 27:475-

479, 1990,

Newsletter of the European Concerted Action on

Cystic Fibrosis, vol. 4, Februmy 1991.

Royal College of Physicians, Prenatal Diagnosis and

Genetic Screening: Community and Service Implications (Imndon: Royal College of Physicians, 1989).

Santis, G., Osborne, L., Knight, R., et al., “Cystic

Fibrosis Haplotype Association and the AF508 Mutation in Adult British CF Patients, ’ Human Genetics

85:424-425, 1990.

Shrimpton, A. E., McIntosh, I., and Broc~ D. J.H.,

“The Incidence of Different Cystic Fibrosis Mutations in the Scottish Population: Effects on Prenatal

Diagnosis and Genetic Counseling,” Journal of

Medicai Genetics 28:317-321, 1991.

Spielberger, C. S., Gorsuch, R. L., and Lushene, R. E.,

The State Trait Anxiezy Inventory (Palo Alto, CA:

Consulting Psychologists Press, 1970).

Vickers, M., Medical Research Council, London,

England, personal communications, June 1991, December 1991,

Watson, E. K., Mayan, E., Chapple, J., et al., ‘ ‘Screening for Carriers of Cystic Fibrosis Through Primary

Health Care Services,’ British Medical Journal 303:

504-507, 1991.

Watson, E. K., Mayall, E. S., Simova, L., et al., “The

Incidence of AF508 CF Mutation and Associated

Haplotypes in a Sample of English Families, ”

Human Genetics 85:435436, 1990.

Watson, E. K., Williamson, R., and Chapple, J.,

“Attitudes to Carrier Screening for Cystic Fibrosis:

A Survey of Health Care Professionals, Relatives of

Sufferers, and Other Members of the Public, ’ British

Journal of General Practice 41 :237-240, 1991.

Williamson, R,, St. Mary’s Hospital Medical School,

London, England, personal communications, June

1991, December 1991.

Williamson, R., Allison, M. E. D., Bentley, S. M. C,, et

al., ‘Community Attitudes to Cystic Fibrosis Carrier

Testing in England: A Pilot Study, ” Prenatal Diagnosis 9:727-734, 1989.
Appendixes
Appendix A

Epidemiology of Mutations for Cystic Fibrosis

The differential distribution of mutations causing

cystic fibrosis (CF) has clear implications for carrier

screening. Besides DF508, which accounts for about 70

percent of CF chromosomes in Caucasians of Northern

and Central European descent, more than 170 mutations

have been identified, and the number increases steadily.

The vast majority of these are rare mutations present in

only a few individuals or families.

Not only are CF mutations heterogeneous, they are

distributed with varying frequencies among populations

according to geographic, ethnic, and racial distinctions;

regional differences within countries also exist. In Europe, DF508 occurs along a decreasing gradient from

north to south (figure A-l); other mutations also occur

differentially among racial and ethnic groups. Denmark

has the most homogeneous CF mutation population in

Northern Europe, with DF508 accounting for about 88

percent of mutations.

International studies continue to document the frequency distribution of DF508 and other mutations (table

A-l). Results are coordinated through international collaborative efforts, including the Cystic Fibrosis Genetic

Analysis Consortium, the European Working Group on

Cystic Fibrosis, and the European Concerted Action on

Cystic Fibrosis.

In the United States and Canada, diverse heritages are

reflected genetically (table A-2): The distribution of

DF508, as an aggregate, is an average of European values.

For example, in North American populations from mixed

European descent, DF508 accounts for 68 to 76 percent of

CF mutations, while the combined European data also

average 68 percent (table A-3). Preliminary studies of

some distinct ethnic groups in North America have

similar profiles to areas of origin in Europe.

By studying markers surrounding the CF locus, researchers believe that the DF508 deletion most likely

resulted from a single mutational event that was subsequently passed along by invading peoples. Some explanations of the distribution patterns of DF508 attempt to

correlate waves of invasions with distribution of the

mutation, although this remains speculation.

Figure A-l—Occurrence of DF508 in Europe

46

SOURCE: European Working Group on Cystic Fibrosis Genetics, “Gradient of Distribution in Europe of the Major CF

Mutation and of Its Associated Haplotype,” Human Genetics 85:436-445, 1990.

–247-
248 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table A-l—Distribution of DF508 in Europe

Frequency Study

of DF508 size

(percent of (number of

cystic fibrosis cystic fibrosis

Country chromosomes) chromosomes) Source

IAntwerp

Bulgaria

Denmark

Finland

France

Albania 75

Belglum 59.5

65

67

77

76

78

80

56

58

Czech and Slovak 68

Federal Republic

Bohemia/Moravia 67

Slovakia 63

87

88

45

45

66

73

79

67

72.5

92

116

124

60

150

146

214

71

96

110

354

NA

46

304

423

40

40

268

271

332

248

258
Appendix A---Epidemiology of Mutations for Cystic Fibrosis ● 249

Table A-l—Distribution of DF508 in Europe-Continued

Frequency Study

of DF508 size

(percent of (number of

cystic fibrosis cystic fibrosis

Country chromosomes) chromosomes) Source

75 422

Britanny (Celtic) 81 224

Lyon 74 230

Paris 70 102

Southern 64 98

Germany

Berlin 70 290

East (former)

West (former)

Greece

Hungary

Ireland,

Republic of

60

60

62

77

77

77

80

54

54

388

518

314

244

234

400

186

194

194

64 66

76 120

76 88

Among Irish Cystic Fibrosis Patients,” Human Genetics 403-404, 1990.

(Continued on next page)
250 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table A-l—Distribution of DF508 in Europe-Continued

Frequency Study

of DF508 size

(percent of (number of

cystic fibrosis cystic fibrosis

Country chromosomes) chromosomes) Source

Israel

Arab

Ashkenazic Jewish

Non-Ashkenazic

Jewish

Arab

Ashkenazic Jewish

Sephardic Jewish

Unclassified

Jew-sh (mixed)

Ashkenazic Jewish

Non-Ashkenazic

Jewish

Italy

32

22

32

38

113

23

40

29

1. Lerer, S. Cohen, M. Chemke, et al., “The Frequency of the DF508 Mutation

on Cystic Fibrosis Chrornmomes in Israeli Families: Correlation to CF Jewish

Haplotypes in Jewish Communities and Arabs,” Human Genetics 85:416-417,

1990.

25

23

35

25

40

95

51

8

127

84

43

T. Shosani, A. Augarten, E. Gazit, et al., “Association of a Nonsense Mutation

(W1282X), the Most Common Mutation in the Ashkenazi Jewish Cystic

Fibrosis Patients in Israel, With Presentation of Severe Disease,” American

Journal of Human Genetics 50:222-228, 1992.

1. Lerer, M. Sagi, G.R. Cutting, et al., “Cystic Fibrosis Mutations DF508 and

G542X in Jewish Patients,’r

Journal of Medical Genetics 29:131-133,

1992.

34

30

42

43

47

55

54

122

284

43 348

50 35

53 350

53 624

Campania

Central/

Southern

Northern

54

45

102

350

40 218

Rome/Verona

Sardinia

42

57

424

42

166

235

Netherlands 75

79

76 152

77 190

Cystic Fibrosis Chrornmomes: Frequency and Relation to Patients’ Age at

Diagnosis,” Human Genetics 85:407-408, 1990.
Appendix A-Epidemiology of Mutations for Cystic Fibrosis . 251

Table A-l—Distribution of DF508 in Europe-Continued

Frequency Study

of DF508 size

(percent of (number of

cystic fibrosis cystic fibrosis

Country chromosomes) chromosomes) Source

Spain

Basque country

Basque

Mixed Basque

Central/

Southern

Continental

Balearic islands

Baiearic Islands

Switzerland

54

Poland 55 22

Portugal 52 82

84

388

388

466

142

30

60

120

45

13

13

334

30

30

25

58

58

39

49

50

51

65

87

58

61

66

58

58

69

Turkey 27

Turkish 27

population

in Germany

Union of Soviet 36

Socialist

Republics (former)

49

Moscow/Odessa 45

United Kingdom 77
252 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Table A-l—Distribution of DF508 in Europe-Continued

Frequency Study

of DF508 size

(percent of (number of

cystic fibrosis cystic fibrosis

Country chromosomes) chromosomes) Source

England 70

70

75

Northern

Ireland

Scotland

Yugoslavia

(former)

Macedonia

75

79

80

70

71.5

78.5

80

54

71

74

74

92

39.5

Slovenia 26

Southern 38

(mixed

population)

210

150

180

186

252

600

108

144

214

195

204

361

238

215

12

38

34

39

The Cystic Fibrosis Genetic Analysis Consortium, “worldwide Survey of the

DF508 Mutation-Report From the Cystic Fibrosis Genetic Analysis Consortium,” American Journal of Human Genetics 47:354-359, 1990.
Appendix A---Epidemiology of Mutations for Cystic Fibrosis ● 253

Table A-2—Distribution of DF508 in

North America

Frequency of DF508

Population (percent)

Caucasian, mixed European ancestry. . . . . 68 to 76

Hispanic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Louisiana French Acadian. . . . . . . . . . . . . . . 69

French Canadian. . . . . . . . . . . . . . . . . . . . . . 54 to 69

Ashkenazic Jewish. , . . . . . . . . . . . . . . . . . . . 26 to 50

African American. . . . . . . . . . . . . . . . . . . . . . . 37

Hutterite. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

SOURCE: Office of Technology Assessment, 1992.

Table A-3-Frequencies of Common

Cystic Fibrosis Mutations

b
Appendix B

Case Studies of Other Carrier Screening Programs

Carrier screening programs have historically been

focused within a particular group---e.g., Tay-Sachs among

Ashkenazic Jews and sickle cell anemia among African

Americans. With cystic fibrosis (CF), the potential target

population is larger and less defined, which may introduce both technical and organizational complexity not

present in past carrier screening. This appendix describes

past carrier screening programs for Tay-Sachs, sickle cell

anemia, and ß-thalassemia. It also delineates the similarities and differences of these programs to reveal considerations for CF carrier screening.

SCREENING FOR

TAY-SACHS DISEASE

Tay-Sachs is a lethal genetic disorder that predominantly

affects Jews of Eastern and Central European descent

(Ashkenazic Jews) and populations in the United States

and Canada descended from French Canadian ancestors;

it also occurs infrequently in the general population. The

disorder affects the central nervous system, resulting in

mental retardation and death within the first 3 to 6 years

of life. Unlike for CF, the means to screen for Tay-Sachs

carrier and affected status have existed for more than two

decades.

Shortly after accurate tests were developed, a number

of large-scale carrier screening programs were initiated,

first in the United States, and then throughout the world.

Carrier screening programs for Tay-Sachs are frequently

considered models for other genetic screening endeavors

(54,64,66). While some of the experiences can be

generalized to other genetic disorders, other facets of

Tay-Sachs carrier screening programs derive from specific aspects of the condition and the populations targeted.

The Disease

TaY-Sachs (also called GM2 gangliosidosis, Type I) is

a progressive, degenerative disorder of the central nervous system. Due to the absence of a particular enzyme,

hexosaminidase A (Hex A), fatty substances-specifically GM2 gangliosides—accumulate in cells throughout

the central nervous system, eventually destroying them.

The process begins prenatally, though the infant can

appear normal for the first months of life. Symptoms

usually begin between 4 and 12 months with an exaggerated startle response, followed by increasing motor

weakness. Blindness, seizures, and continual decline into

a vegetative state ensue until the child dies. No cure exists

(19).

Genetics of Tay-Sachs Disease

Like CF, Tay-Sachs is a single gene disorder inherited

in an autosomal recessive pattern; that is, only a child

receiving a defective copy of the gene from each parent

will be affected; carriers have no clinical symptoms.

Among the general population, Tay-Sachs mutations are

rare, occurring with a carrier frequency of 1 in 167, giving

rise to 1 in 112,000 affected births, The disease is

significantly more common, however, among Ashkenazic

Jews: the carrier frequency is 1 in 31 and birth incidence

is 1 in 3,900 (77). Prevalence in Ashkenazic Jews is a

function of ethnic background, and is unrelated to

religious practice, Elevated incidence of variant alleles are

also found among Moroccan Jews (97), FrenchCanadians (l), and a distinct population of Louisiana

French Acadians (41).

In 1969, scientists identified the lack of Hex A as the

underlying metabolic defect in Tay-Sachs disease (60). A

year later, an enzymatic assay was developed to measure

Hex A activity. Application of this test to known carriers

revealed intermediate activity of the enzyme in these

individuals, which led to the assay for carrier identification among those without family histories (59).

Tay-Sachs carrier screening is performed on blood

serum, although for pregnant women, women using oral

contraceptives, and persons with liver disease, the blood

serum test does not yield accurate results. Instead, white

blood cells, platelets, or tears are used; such methods are

more time-consuming and costly. The biochemical assay

also can be used to detect affected fetuses through either

amniocentesis (79) or chorionic villus sampling. This

assay has had significant false positive carrier rates but

lower false negative rates (80).

In the mid-1980s, characterization of the Hex A gene

structure and mutations led to the possibility of DNAbased Tay-Sachs screening and diagnosis. Three distinct

mutations account for 90 to 98 percent of Tay-Sachs

chromosomes in this population (28,62,94); one—a 4

base pair insertion-is present in over 70 percent of

Tay-Sachs Ashkenazic alleles. In contrast, among nonAshkenazic carriers, the three mutations comprise about

20 percent of defective mutations (28,62,94). For Moroccan Jews, a single base pair deletion predominates (56),

while in French-Canadians, multiple mutations are present (29). Preliminary results in the Imuisiana French

Acadian population indicate the presence of two alterations correlated with Ashkenazic carrier alleles (50).

Additionally, one of the prevalent Ashkenazic mutations

results in an “adult-onset” form of the disease (94).

–254-
Appendix B-Case Studies of Other Carrier Screening Programs ● 255

DNA analysis is useful in confirmatory and family

studies and is being tested as a carrier screening method

in some centers. Currently, DNA assays allow confirmation of diagnosis, reducing levels of both false positives

and false negatives (62,94). In the future they might

replace the enzymatic assay.

Screening Programs

Initial awareness of Tay-Sachs centered in Jewish

communities; hence, screening programs (using biochemical assays) for carrier status originated there. After these

efforts were launched, similar programs spread to areas

where French-Canadians clustered and, most recently, to

parts of Louisiana, The almost immediate implementation

of carrier screening programs among Ashkenazic Jews

was

●

●

●

●

facilitated by a number of factors:

occurrence of the disease is concentrated in a defined

population;

determination of the carrier state is easy and relatively inexpensive;

at-risk pregnancies can be monitored through prenatal diagnosis of the disease (34); and

public funding or subsidies were available-e. g.,

through the National Sickle Cell Anemia, Cooley’s

Anemia, Tay-Sachs, and Genetic Diseases Act

(Public Law 94-278).

Tay-Sachs Carrier Screening Programs

Tay-Sachs carrier screening began in 1971 in the

Baltimore, MD-Washington, DC Jewish populations at

the behest of the Jewish communities (34). The pilot

program involved community outreach: 14 months of

organizational planning, technical preparation, and education of medical and religious leaders preceded massive

public education campaigns. Every aspect was carried out

within the community, from planning to sample collections, which were held in synagogues, high school

gymnasiums, and Jewish community centers (34). Eighteen hundred people showed up in one day for the first

screening; in under a year, 5,600 individuals were

screened, and 245 carriers identified (34,35).

Following the success of this effort, Jewish communities throughout the United States and Canada implemented similar endeavors. By 1976, 52 cities in the

United States, and others in Canada, England, Israel,

South Africa, and Japan were conducting carrier screening programs (34). Many centers followed the initial

protocol, adapting specifics to individual locations. Most

changes were made in the target population group and in

TAY-SACHS FACTS:

● TAY-SACHS DISEASE IS AN INHERITED GENETIC

DISORDER OF INFANCY

● A CHILD WITH THE DISEASE CAN BE BORN TO

HEALTHY PARENTS WHO ARE CARRIERS OF THE

TAY-SACHS GENE

● ANYBODY CAN BE A CARRIER – CARRIER RATE IS

1 :150 IN THE GENERAL POPULATION AND 1:30 IN

THE JEWtSH POPULATION

● EARLY CARRIER DETECTION CAN

PROTECT FUTURE GENERATIONS

WED., MAY 16 11:OOam-2:OOpm Tresidder Union,

oak Lounge West

530pm-7 30pm Business School,

Room 54

THURS. MAY 17 8:OOam-10:OOam Med. Center,

M106 (Med. Stu. Lounge)

11:OOam-2:OOpm Tresidder Union,

Oak Lounge West

(over 17’ and non-pregnants only, please)

Sponsored by: AEPi; Hillel; Stanford Genetic Counseling, Dept of Gyn/OB; Cowell Health Promotion Program

– BE SAFE – BE TESTED –

Take the Carrier Detection Test

For Additional Information Call

NORTHERN CALIFORNIA TAY-SACHS PREVENTION PROGRAM – (415) 658-5568

This is a public service program supported by the State of California Department of Health

Photo credit: Alpha Epsilon Pi

An advertisement for Tay-Sachs carrier screening.
256 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

emphasis on public or physician education. Three main and Jewish community centers advising them to refer

approaches evolved: married couples, either pregnant or planning a pregnancy,

●

●

●

to physicians for screening. In 1983, a unique program,

educating and screening the entire community (mass Chevra Dor Yeshorirn, in New York City’s Orthodox

screening); Jewish population began screening people prior to

targeting couples of reproductive age, usually with

the involvement of physicians; and

arranged marriages to ensure that no marriages would

occur between carriers (box B-l).

screening high school and college students.

Students. A different approach was launched in

Mass Screening. Mass screening programs essentially

followed the prototype of the Baltimore, MDWashington, DC endeavor. In a south Florida area with a

high concentration of Ashkenazic Jews, for example, a

program involving leaders of the local community,

parents of children with Tay-Sachs, and the Department

of Pediatrics at the University of Miami School of

Medicine was organized in 1973. In 1974, the steering

committee overseeing the Florida effort decided to

reemphasize mass screening sessions, and established

small, local clinics (including synagogues and colleges)

where screening sessions could be coordinated with local

blood banks’ visits to the community. Though screening

was available to all individuals, young, single persons

were counseled that it might be more effective to delay

screening until after marriage, when reproductive decisions would be more pertinent (93).

Couples of Reproductive Age. In 1977, clinical

chemists in Akron, OH designed a program that focused

on educating family physicians and minimizing public

education (63). Information was disseminated to rabbis

Montreal, Canada in 1974. -A school-based screening

program, operated by physicians and paramedical personnel, garnered participation of 75 percent (48). An 8-year

followup study indicated that Canadians screened in high

school had largely positive attitudes toward genetic

screening long after the experience, and made appropriate

use of the results (82,83,106). Others criticize the

followup study for underestimating the forgetfulness of

the adolescents screened (91). Though voluntary genetic

screening of high school students is considered acceptable

and successful by many in the Montreal community (83),

some outside the community accuse the program of

coercion (30).

Tay-Sachs Screening Today

Through 1987, 600,000 people had been screened

through voluntary programs in the United States (55).

Almost 22,000 heterozygotes had been identified, and

more than 1,400 pregnancies were monitored. Over 200

affected fetuses were detected and more than 1,000

healthy babies were born from at-risk pregnancies (55).

Box B-1-Chevra Dor Yeshorim Tay-Sachs Program

Chevra Dor Yeshorim, which originated in New York City’s OrthCdox Jewish community, is a unique

Tay-Sachs screening program. The elevated incidence of Tay-Sachs in this population, combined with religious

beliefs opposing abortion and contraception, led community leaders to conclude that preventing Tay-Sachs was

possible only by avoiding reproduction between carriers (52). Such reproduction could be avoided because this

Orthodox Jewish community arranges marriages through matchmakers.

In 1983, the Committee for Prevention of Jewish Genetic Diseases formed Chevra Dor Yeshorim, which still

operates today. All marriageable people are assigned a number and screened for Tay-Sachs carrier status at a local

center (52). No one is informed of his or her result, which is filed by numik only. When a marriage is proposed,

the matchmaker calls the center with the prospective couple’s numbers and is informed whether the proposed match

involves two Tay-Sachs carriers; if the match does not, marriage plans proceed. If the match involves two carriers,

the matchmaker tells the two families to contact the center, where the families are informed that both children are

carriers and referred to counseling. Carriers thus learn their status only if they match with another carrier families

can report the match has failed for other reasons and look for new matches. This system of anonymity is employed

because of historical stigmatization of carriers (52).

Chevra Dor Yeshorim has eventually become an adolescent rite of passage. Similar programs have been

developed in California, Tennessee, Michigan, Florida, Maryland, Massachusetts, Illinois, Montreal, Israel, Europe,

and other communities (45). By 1992, more than 30,000 people have been screened through such programs. More

than 7,000 inquiries have been made and 47 prospective matches between Tay-Sachs carriers identified and halted

(45).

SOURCE: OffIce of Technology Assessment, 1992.
Appendix Mase Studies of Other Carrier Screening Programs ● 257

Today, the focus has changed somewhat from the early

mass education and screening approach, with over 100

hospitals and clinics nationwide offering screening on a

continual basis. According to the National Tay-Sachs and

Allied Diseases Association (NTSAD), a major aim

“continues to be the promotion of genetic screening

programs nationally through affiliated hospitals and

medical centers, and through [NTSAD’S] local chapters

and community organizations” (55).

A program in Toronto, Canada illustrates some general

trends in Tay-Sachs carrier screening. Begun in 1972 as

a community outreach program along the lines of the

Baltimore, MD-Washington, DC prototype, it faced

lagging community attendance by the end of the decade.

By 1978, the orientation changed from mass screening to

one of case finding, where physicians referred patients for

screening on an individual basis (14,15,47). In this

manner, 600 to 700 individuals are screened each year.

Nearly two-thirds are pregnant at the time of screening,

suggesting that determination of carrier status is being

viewed as part of prenatal care rather than preconception

planning.

Though outreach efforts are directed beyond the Jewish

community, knowledge of Tay-Sachs is generally confined to this population. When multiple cases of Tay -

Sachs surfaced in a rural, Catholic community in

Louisiana, NTSAD and Tulane University organized a

mass education and screening program (41). NTSAD

continues public education efforts through nationwide

mailings to community and religious organizations and to

college, high school, and grammar school libraries.

SCREENING FOR

SICKLE CELL ANEMIA

If Tay-Sachs screening is often held as an example of

a successful screening campaign, early sickle ceil screening efforts are frequently cited as ‘‘screening gone

wrong. Like Tay-Sachs, sickle cell anemia is an

autosomal recessive condition generally affecting a particular population—for sickle cell anemia, people of

African descent. Sickle cell anemia impairs red blood cell

flow through the circulatory system, causing complications in organ systems throughout the body.

As for Tay-Sachs, massive screening programs for

sickle cell were undertaken in the United States in the

1970s. Sickle cell programs, however, differed immensely from the Tay-Sachs program in a variety of ways.

Screening was mandatory in some States, and there was

neither treatment nor prenatal diagnosis. Early programs

also suffered from misinformation and discrimination

against carriers.

Figure B-l—Normal and Sickled Red Blood Cells

In sickle cell anemia, many red blood cells are distorted from their

normal round shape (top), into the shape of a crescent or sickle

(bottom). These distorted cells can obstruct smaller blood vessels

or be removed too rapidly by the spleen.

SOURCE: M. Murayama, National Institute of Arthritis, Musculoskeletal,

and Skin Diseases, National Institutes of Health, Bethesda, MD,

1992.

The Disease

The sickle cell mutation affects hemoglobin (Hb), the

oxygen-carrying molecule in the blood stream. Hb is

found in the red blood cells and can be of a variety of

types. Fib A is found in healthy red blood cells; Hb S

occurs in the red blood cells of sickle cell anemia patients.

Hb S causes the cells to become deformed and sickle

shaped (figure B-l). Sickled red blood cells become

trapped, decreasing red blood cell survival and, therefore,

oxygen transport. Individuals with sickle cell anemia are

susceptible to episodes of extreme pain in the limbs, back

abdomen, or chest, which are thought to be caused by

blockages of the deformed red blood cells in the

circulatory system, These crises occur as often as once a

month to once every other year and can last from 3 days

to more than 3 weeks. Lack of oxygen in the spleen,
258 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

kidneys, bones, and joints can also damage these organs

and tissues. Eight to 30 percent of children with sickle cell

anemia die in the first years of life from complications of

severe bacterial infection (25). However, intensive antibiotic treatment-if begun early enough-imparts some

resistance to these conditions (25). No cure exists for

sickle cell anemia. Unlike Tay-Sachs, sickle cell anemia

does not involve mental retardation.

Genetics of Sickle Cell Anemia

Like CF and Tay-Sachs, sickle cell anemia is a genetic

disorder inherited in an autosomal recessive pattern. A

person with two copies of the sickle cell mutation is

homozygous and has sickle cell anemia. A person with a

single copy is heterozygous and is said to be a sickle cell

carrier or to have sickle cell trait. The red blood cells of

people with the sickle cell trait contain both Hb A and

Hb S. These individuals do not have sickle cell anemia

and are considered to be healthy with a normal life

expectancy (88,101). Some clinical abnormalities have

been found in people with sickle cell trait including

defects in urine concentrating ability and occasional bouts

of blood in the urine (88), Under extremely low-oxygen,

high-exertion conditions, minimal sickling of red blood

cell can occur (36).

I I ,

Photo creadit: Howard University

Patient education brochures describing sickle cell

anemia and sickle cell trait.

The precise difference between Hb A and Hb S was

elucidated in 1956 (57); since then, the specific mutation

causing these mutations has been found. The genetic basis

of sickle cell is rare: One base change accounts for all

cases of the disorder (57). Abase change of an adenine for

a thymine in the ß-globin gene produces a single amino

acid difference of the 146 amino acids in the ß-chain—

one of the two protein components of Hb.

Although the incidence of the sickle cell mutation is

high in Greeks, Italians (particularly Sicilians), Eti-Turks,

Arabs, southern Iranians, and Asian Indians, the highest

frequency occurs in Africans and their descendants (7).

One in 400 African American newborns has sickle cell

anemia (32), and 1 in 10 or 11 has sickle cell trait

(3,57,96).

Diagnostic procedures for sickle cell anemia evolved as

knowledge of the biochemistry of Hb increased. Discovery of the differential electrophoretic mobility of Hb S and

Hb A permitted testing of blood samples. The presence of

only Hb A indicated noncarrier status, only Hb S

indicated sickle cell anemia, and the combination of

Hb A and Hb S in an individual indicated sickle cell trait.

Restriction fragment length polymorphism analysis has

had an important impact on diagnosis of sickle cell

disease and trait, especially in the prenatal diagnosis of

affected fetuses by amniocentesis and chorionic villus

sampling. In the early 1980s, a restriction enzyme, Mst II,

that recognizes a sequence at the site of the sickle cell

mutation itself was found (61). Since 1982, researchers

have performed this procedure with 100 percent informativeness and rare errors (39). Diagnosis no longer depends

on having informative family members. DNA diagnosis

to detect sickle cell has been shown to be 100 percent

informative and 99 percent reliable (43). Additionally,

polymerase chain reaction can now be used with nonradioactive, enzyme-labeled, allele-specific oligonucleotide

probes in dot-blot format (76).

Screening Programs

In the early 1970s, 16 States and the District of

Columbia enacted laws to identify people with sickle cell

trait and sickle cell anemia so that carrier couples could

be informed of their risks of having affected children.

Most laws were drafted and promoted by African

American legislators at the height of the civil rights

movement. At first glance, they offered an inexpensive

benefit to African American citizens (65). Depending on

the States, screening was mandated for newborns, preschool children, pregnant women, couples applying for

marriage licenses, inmates of State institutions, or some

combination of these groups. Some States mandated that

tests be offered, while others mandated screening.

Many aspects of State sickle cell screening laws

generated public critique. Statutes consistently contained
Appendix B--Case Studies of Other Carrier Screening Programs ● 259

blatant medical and scientific errors including calling for

immunization for sickle cell anemia. Some States classified sickle cell carrier status with having sexually

transmissible diseases on marriage licenses; others called

it a communicable disease (65). Almost every State law

failed to insist on using the most sensitive assay available.

Controversy also focused on the racial distribution of

sickle cell mutations and the target screening population.

Sickle cell anemia was considered a “Black Disease”

(32). The laws were seen by many citizens as racist

eugenic measures aimed at reducing the number of

marriages between carriers and decreasing the number of

pregnancies at risk for affected children of a minority

population. The fact that the programs were largely

designed and operated by Caucasians fueled proclamations of genocide.

Most State laws failed to provide adequate education

and counseling for persons with sickle cell anemia and

trait. The most common error conferred disease status on

those who were carriers. Those diagnosed with sickle cell

trait were often told they could not have children, that

childbirth would be hazardous, or other untruths. Only 4

of 13 programs mentioned counseling of any sort. People

were often confused about which condition they had—

sickle cell disease or sickle cell trait—which led to

increased anxiety.

State laws also failed to provide public education to

guard against discrimination and stigmatization. By 1972,

for example, at least one flight attendant had been

grounded (32). Stories of job and insurance discrimination multiplied as screening programs proliferated. Additionally, too little concern was expressed over confidentiality of results, Some States required that positive test

results be filed with the State’s public health entity.

National Legislation

In 1971, President Nixon spoke of the problem of sickle

cell anemia and the need for more research and education.

The 1972 National Sickle Cell Anemia Control Act

authorized $85 million over 3 years for the ‘‘establishment and operation of voluntary sickle cell anemia

screening and counseling programs, ’ and to ‘‘develop

information and educational materials relating to sickle

cell anemia and to disseminate such information and

materials to persons providing health care and to the

public generally” (Public Law 92-294). Some $30

million was allocated for research on the disease and for

development of educational, screening, and counseling

programs. Applicants for Federal funds were required to

meet certain standards and to ensure confidentiality of all

medical and counseling records. The law also promised

community participation: African Americans delivering

the service to African Americans.

Sickle Cell Screening Today

By 1973, laws in eight States had been repealed (57).

By 1977, more than one-third of States had enacted laws

under the National Sickle Cell Anemia Ccntrol Act (65).

Mandatory screening was eliminated, and the need for

adequate genetic counseling, public education, and confidentiality of test results was recognized (65). Nevertheless, discrepancy between the ideal and actual practice

existed, as criticism focused, in the late 1970s, on a

continued lack of ‘‘community participation’ and accusations of Federal money granted disproportionately to

white institutions (65),

Today, sickle cell screening is often done routinely on

pregnant women as part of routine blood workup and on

newborns (3,23). Prenatal sickle cell screening infrequently results in selective pregnancy termination (103).

Forty States screen newborns for sickle cell anemia (103),

detecting babies with sickle cell anemia and babies who

are carriers, Some States screen all newborns, some target

a particular population, and some have voluntary screening that varies from hospital to hospital (103). Some

newborn screening is done without informed consent, but

with counseling of the parents if carrier status is detected

(3).

SCREENING FOR

ß-THALASSEMIA

ß-thalassemia, also known as Cooley’s anemia, thalassemia major, target cell anemia, and Mediterranean

anemia, is an autosomal recessive condition for which

carrier screening has been undertaken. ß-thalassemia

clusters in particular ethnic groups—people of Mediterranean, Middle Eastern, Asian Indian, Chinese, Southeast

Asian, and African descent (7). Legislative action concerning ß-thalassemia has occurred both in the United

States and abroad. Screening for a-thalassemia, a related

disorder, was first introduced in 1975 and continues today

in some parts of the world (box B-2). Many European

programs emphasize hemoglobinopathy screening encompassing all clinically significant a and ß alleles and

their combinations (103).

The Disease

ß-thalassemia is one of the most common genetic

disorders in the world (92). Like sickle cell anemia, the

condition affects the Hb of red blood cells. In ßthalassemia, the amount of Hb is diminished, causing red

blood cells to be smaller and have a‘ ‘target” appearance.

Severe anemia, frequent infections, spleen enlargement,

growth retardation, and marrow hypertrophy are all

characteristics of the disorder (57). Death usually results

from iron toxicity, most often in childhood. Therapy for

ß-halassemia includes transfusions, folic acid supplementation, and intensive treatment of infections. Transfu-
260 ● Cystic Fibrosis and DNA Tests: Implications of Carroer Screening

Box B-2---a-Thalassemia

a-thalassemia is another genetic condition often included in carrier screening programs. Like ß-thalassemi~

it is an autosomal recessive disorder affecting hemoglobin (Hb) production. The level of a-globin, a component of

Hb, is decreased, resulting in abnormal Hb molecules: Hb H and Hb Bart. It is the most common genetic disease

in some Chinese provinces and is found throughout Southeast Asia and the Mediterranean. According to the World

Health Organization, 10,000 babies are born with a-thalassemia each year in Asia (42). a-thalassernia also affects

people of African descent (7).

a-thalassemia results from mutations in the a-globin genes (87). While there is one ß-globin gene in the human

genome, there are two a-globin genes. The most severe type of a-thalassemia is caused by homozygous deletion

of both a-globin genes. This condition, called hemoglobin Bart’s hydrops fetalis, generally leads to intrauterine

death (57,98) and is the primary cause of stillbirth in Southeast Asia (57). Three to five percent of African Americans

are heterozygous carriers of mutations for both a-thalassemia genes, and about 26 percent are heterozygous carriers

for mutations in one of the a-thalassemia genes (6).

Prior to DNA analysis, diagnosis relied on assaying the presence of Hb Bart in cord blood of babies suspected

to have dmlassemia. Identifying carriers by determination of mean corpuscular volume (MCV) and globin chain

electrophoresis was inexact. Today, DNA technologies have increased the speed and efficacy of prenatal and carrier

screening for a-thalassemia (44).

Carrier screening for a-thalassemia occurs worldwide (100). One program is currently undenvay in Hong

Kong, where 98 percent of the population are ethnic Chinese from South China, with a carrier frequency of 3 percent

(12). Public education, and formal organization of screening, counseling, and referral were required to make the

program successful (12). Today, both carrier screening and prenatal diagnosis appear to be well accepted in Hong

Kong (12). A similar effort is advancing in Guangdong Province in southern China (107), where the carrier

frequency is about 5 percent.

a-thalassemia carrier screening has also been conducted in the United States. In the 1980s, researchers in

southern California educated a Southeast Asian population about screening through the community’s churches.

Thalassemia screening was performed on a cross-section of the population and on newborns using MCV indices

and Hb electrophoresis. Approximately 8 percent of more than 600 individuals were found to be carriers.

Today—although the program is no longer operating because Federal funding expired-overall awareness of

a-thalassemia appears to have been maintained among physicians, and screening now targets pregnant women in

obstetricians’ offices (21).

One study in Hawaii assessed consumer attitudes towards thalassemia screening (105). As part of the Hawaii

Hereditary Anemia Project, 862 a- and ß-thalassemia carriers who were identified through the project were

surveyed about feelings of stigmatization and attitudes toward knowledge gained. Researchers concluded that

learning carrier status provoked little anxiety (except in less educated populations) and provided meaningful

benefits (105). Researchers in Rochester, NY have found that the percentages of people seeking an explanation of

the test result, having the partner screened, and undergoing prenatal diagnosis are all higher among Southeast Asians

than non-Southeast Asians (72).

SOURCE: Office of Technology Assessment 1992.

sions, however, can result in hemochromatosis (iron mutations, symptoms range from mild to severe (9). Some

overload), which can be improved slightly by using

chelating agents to reduce excess iron. Splenectomy—

removal of the spleen—is indicated if signs of hypersplenism exist and is performed preferably after age 5

(57),

Genetics of ß- Thalassemia

Like sickle cell, ß-thalassem.ia is an autosomal recessive disease caused by mutations in the ß-globin gene.

Unlike sickle cell, however, several mutations lead to

ß-thalassemia (37). Depending on the number and type of
Appendix B---Case Studies of Other Carrier Screening Programs ● 261

American, African American, or Asian American (74),

those populations generally considered at high risk. This

finding argues in favor of screening all pregnant women,

not only those usually regarded as at elevated risk based

on ethnicity or race. Eighty-six percent of women who

were counseled about their hemoglobinopathy carrier

status said they wanted their partners screened, 55 percent

had their partners screened, and 47 percent of carrier

couples identified underwent prenatal diagnosis. Thus,

unselected patients in a primary care setting in the

Rochester region, even though pregnant, were receptive to

and utilized genetic information (74). The researchers

concluded that genetic screening in such a setting has

many advantages over that in non-health-care settings,

including comprehensive coverage of the population,

screening at a time appropriate or relevant for the

individual, and increased likelihood of appropriate medical followup (69).

The Federal Government has also been involved with

ß-thalassemia screening. In 1972, the National Cooley’s

Anemia Control Act (Public Law 92-414) was introduced

and sponsored by legislators of Mediterranean heritage. It

authorized $3 million for ß-thalassemia screening, treatment, and counseling programs, $3 million for public

education, and $5.1 million for disease research over a

3-year period (65).

Canada

A program for ß-thalassemia prevention comprising

education, population screening for carriers, and reproductive counseling has been carried out in Canada (81). In

a 25-month period (1979-81), 6,748 persons, including

5,117 high school students, were screened for ßthalassemia trait using MCV indices; the participation

rate was 80 percent(81 ). Researchers surveyed 60 carriers

and 120 noncarriers among the high school student

population, and most carriers told parents (95 percent) and

friends (67 percent) the test result. Most carriers (91

percent) reported they would ascertain their spouses’

genotype; 95 percent approved of the screening effort

(81).

Sardinia

ß-thalassemia is a significant health problem. One

couple in 80 is a carrier couple—i.e., at 1 in 4 risk of an

affected pregnancy. Prior to screening, 1 in 250 live births

had ß-thalassemia. Most ß-thalassemia cases in Sardinia

are severe-i. e., ß-globin chains are absent. About 96

percent of the ß-thalassemia mutations in this population

are of a single type, and another mutation accounts for 2.1

percent of the remaining mutations (1 1).

In 1976, the region’s Department of Public Health

initiated a voluntary program to control ß-thalassemia in

Sardinia based on carrier screening, genetic counseling,

and prenatal diagnosis. General practitioners, obstetri-
262 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

cians, and paramedics were trained at specific educational

meetings about the philosophical and technical aspects of

the program. The program was targeted toward young

unmarried men and women, married couples, and pregnant women. When a carrier was identified, the professionals urged that other family members also consider

testing (1 1).

Prior to implementing the program, a mass media

educational campaign geared to the general public was

launched. About 47 percent of couples and 65 percent of

singles screened said they learned of the program through

this campaign. Screening was performed first on one

member of a couple. If that individual was positive, his or

her partner was screened. Prenatal diagnosis was also

performed (1 1).

To date, 24 percent of Sardinia’s population has been

screened, and 85 percent of the theoretical number of

carrier couples (+/+) in the population have been identified. In large part, this high efficiency results from

followup screening of carriers’ family members (1 1).

Sixty-five percent of those screened in 1980 were

pregnant women. By 1990, only 30 percent were pregnant, demonstrating a trend in increased knowledge--i. e.,

individuals came in for screening prior to conception. The

incidence of ß-thalassemia in Sardinia has declined from

1 in 250 live births in 1974 to 1 in 1,200 in 1991, an

effective prevention of 90 percent of predicted cases (11).

Of babies born with ß-thalassemia, 67 percent were born

to parents who were unaware of the disease and of carrier

screening, 20 percent were to parents who, for ethical

reasons, decided against abortion after prenatal diagnosis,

and 13 percent were cases of false paternity (1 1).

An important early result of the program was the

impact on carriers. Many had difficulty finding jobs,

chiefly because the national army is the predominant

employer in Sardinia and refuses to employ ß-thalassemia

carriers due to a misunderstanding about carrier status.

Ongoing efforts to educate the army appear likely to

reverse this practice in the near future (1 1). ß-thalassemia

screening in Sardinia is currently moving to encompass

the school-aged population (1 1).

Cyprus

In Cyprus, 1 in 7 individuals is a carrier, and 1 in 1,000

Cypriots is a patient under treatment for ß-thalassemia

(2). In the early 1970s, the realization that demand for

treating this single disease could outstrip resources for all

health care led to the development of a national carrier

screening effort. Undertaken with World Health Organization support, the program consisted of public education,

population screening for carriers, genetic counseling for

carrier couples, prenatal diagnosis, and premarital screening (2).

An unusual compliance mechanism is one facet of the

Cyprus program. The Greek Orthodox Church recognized

the problems of the high incidence of ß-thalassemia

births, but was reluctant to endorse pregnancy termination

to prevent such births. In 1983, however, the Church

agreed that, before the Church would bless a marriage or

engagement, a couple would be required to present a

certificate proving they had been screened and had

received genetic counseling. With the Church’s cooperation, the number of people screened skyrocketed from

1,785 in 1977 to 18,202 in 1983. Today, 10,000 to 11,000

people are screened annually. Since most couples of

reproductive age have been screened, attention now

focuses on single people. Since 1985, a 20 percent fall in

the expected proportion of +/+ couples has been noted,

perhaps indicating that carriers are avoiding marriage to

other carriers (2).

As in Sardinia, the number of newborns with ßthalassemia has fallen dramatically. In 1974,53 of 8,594

births were affected: From 1986 through 1990, there were

five, for a prevention rate of 97 percent. Ninety percent of

the 69 affected babies born between 1978 and 1980

resulted from lack of knowledge among the public and the

medical profession about the Cyprus carrier screening

effort. Two births were due to refusal of prenatal

diagnosis on religious grounds, two were laboratory

errors, and one was parental choice after positive prenatal

diagnosis.

The program’s success is attributed to several factors,

including extensive and continuous public education,

small population size, and homogeneity of the population

(2). Time spent on counseling is much less today than

when the program was initiated-a direct result of

increased public education. A newer program is under

way in Turkish Cyprus.

Other ß-thalassemia Screening Programs

Screening programs for ß-thalassemia in the United

Kingdom (58) incorporate treatment and prevention into

general health care. Primary health care, peripheral

centers, and reference centers coordinate the program’s

efforts. Individuals learn about the screening through

schools and public information posters. Community

involvement, particularly through parents’ and patients’

associations is an important component, and a detailed

education program provides effective information about

genetic risks and services. Fewer ß-thalassemia births

have been avoided in the United Kingdom than in Cyprus

or Sardinia, chiefly because of the large population size,

the occurrence of ß-thalassernia in ethnic minorities

scattered throughout an indigenous population, and the

beliefs of many of those at risk that prenatal diagnosis and

abortion are socially and religiously unacceptable (58).

Southeast Asia, Hong Kong, East Mediterranean coun-
Appendix B---Case Studies of Other Carrier Screening Programs ● 263

tries, and South China have ß-thalassemia carrier screening programs (12,46,107).

LESSONS FOR CYSTIC FIBROSIS

CARRIER SCREENING

The Tay-Sachs, sickle cell anemia, ß-thalassemia, and

ß-thalassemia experiences offer lessons that might be

applicable to routine carrier screening for CF. These

lessons involve five principal aspects of the programs

described in this appendix:

nature of participation,

setting and fiscal support,

target population,

public education, and

counseling carriers and at-risk couples.

Nature of Paticipation

Participation in the programs described in this appendix was voluntary or mandatory. The Tay-Sachs expedience offers a model of voluntary participation, which

contributed to its efficacy and success—both in reducing

disease and in avoiding stigmatization (54,66). It is

noteworthy, nonetheless, that one survey found that

nearly half of participants in one Tay-Sachs program felt

screening should be mandatory, although the breakdown

of carriers and noncarriers expressing those opinions was

not measured (13).

The sickle cell experience, on the other hand, included

some mandatory State screening of people in schools or

correctional institutions, or of couples applying for

marriage licenses. Such mandatory participation was

viewed as a contributing factor in the widespread failure

of these efforts (65,66). ß-thalassemia programs in the

United States and abroad have used the voluntary

approach and have been generally successful (2,11,74,105).

ß-thalassemia programs in the Mediterranean that use a

quasi-mandatory approach through the involvement of

the Greek Orthodox Church also have been successful in

reducing disease. Although stigmatization appeared to be

an issue initially, it seems to now be obviated (2). The

success of these mandatory programs, however, can be

attributed mainly to the cultures of Cyprus and Sardinia

and is likely not applicable to carrier screening in the

United States.

Thus, success of voluntary initiatives and the failure of

mandatory programs (excluding the Cyprus example)

lead many to conclude that voluntary participation for CF

carrier screening is essential. The National Institutes of

Health (NIH) Workshop on Population Screening for the

Cystic Fibrosis Gene recommended that screening be

voluntary (4).

Setting and Fiscal Support

The environment in which a genetic screening program

is administered also affects its success and acceptance.

Tay-Sachs carrier screening was community-based. Leaders within the Jewish community became leaders of the

screening programs, which were offered through synagogues, storefronts, and community centers. The community was involved in all aspects of the program. For CF,

however, the target population is larger and more diffuse,

with a wide range of religious beliefs. Thus, it would be

an ill fit to organize CF carrier screening solely through

religious centers.

In stark contrast, the sickle cell anemia programs were

run largely by the State and Federal governments, their

contractors, and grant recipients. During a time of tension

over civil rights, Caucasians from outside of the community generally controlled screening, which was viewed

extremely negatively by the African American community. The resulting lack of support by the targeted

population doomed sickle cell screening programs to

failure.

ß-thalassemia programs in the United States have been

more diverse, involving primary care physicians in

neighborhood health centers, a large HMO, hospital

prenatal clinics, a family medicine program, and private

practice. The particular setting seems less important to

success than other factors, (e.g., patient and provider

education> although a primary care clinical setting is

desirable (69)—and likely will prove most appropriate to

CF carrier screening. (ß-thalassemia experiences in Europe revolve around national health care systems, making

it difficult to compare setting and funding to U.S.

experiences.)

Beyond the particular setting is the issue of funding for

organizing and maintaining the effort. Historical perspectives probably apply least in this area. Most efforts

launched in the 1970s and 1980s involved some degree of

public funding. With respect to routine CF carrier

screening in the United States, the funding issue is

complex, but direct funding in the manner of Tay-Sachs,

sickle cell, or the thalassemias is unlikely to materialize

beyond the current NIH pilot projects (ch. 6). Thus, to the

extent that direct public subsidy contributed to the success

of past screening, routine CF carrier screening will

unlikely realize such a benefit.

Target Population

Tay-Sachs programs targeted a narrow slice of the U.S.

population. The population was easily identifiable, largely

urban, educated, and receptive to screening and reproductive options; all are population characteristics often cited

as beneficial to a program’s success (34). Sickle cell

programs targeted African American communities at the
264 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

height of the civil rights movement, causing considerable

controversy about segregation, discrimination, and stigmatization. Racial tensions created by singling out a

population already historically discriminated against

stress the importance of prior awareness of the implications of focusing on members of a particular group and

their potential reactions to screening.

The age and sex of the screened population also have

implications for CF carrier screening. With the ability to

perform prenatal diagnosis, much attention focuses on

screening pregnant women (95). Some argue that screening during pregnancy offers the advantages of immediate

interest in knowledge of genetic information and comprehensive coverage of the population (75). Disadvantages of

screening during pregnancy include eliminating the

option to avoid conception, so that prenatal fetal testing

might be perceived as necessary. Or, it might be too late

in a pregnancy for prenatal diagnosis even if desired.

Some also believe that carrier identification can be too

anxiety-producing during pregnancy to be efficacious.

Others argue that screening women first can be perceived

as eugenic screening for breeding fitness (102).

Many studies have attempted to ascertain the optimal

group for carrier screening: newborns, students, primary

care recipients, pregnant women, couples planning to

marry, or married couples (13,16,17,99,106). The studies

often conflict: Each group offers advantages and disadvantages that vary by disease, available technology, and

manifestations of the disease (ch. 6). Thus, the optimal

population for CF carrier screening remains a topic of

debate. Additionally, while CF mutations have a high

prevalence in one racial group-Caucasians-the ethnic

diversity of this population in the United States poses a

challenge that did not exist for previous screening efforts.

Beyond diversity per se, many Americans do not know

specifics of their ethnic backgrounds, knowledge which

might assist in more precisely assigning risks (96).

Further, CF also occurs, albeit less frequently, in Asian

Americans and African Americans. The extent to which

routine screening within these two groups is appropriate

is also an issue.

Public Education

Consumer knowledge--both about medical aspects of

the specific genetic condition and the meaning of carrier

status—is key. Conditions that affect mental function,

such as Tay-Sachs, appear to have a greater acceptance of

carrier screening and prenatal diagnosis (20,22,26). The

high acceptability of screening that resulted from public

education for Tay-Sachs might be less informative for

routine CF carrier screening, for example, although the

mechanism of providing the education could be illustrative. Likewise, CF carrier screening might not serve as a

good indicator of future screening for disorders such as

fragile X syndrome (box B-3).

Stigmatization of carriers, widely cited as a negative

outcome of genetic screening (27,30,67), is largely

attributed to ignorance within both the community being

screened and the general population. In contrast to

acceptability, lessons about the importance of public

education to avoid stigmatization can be gleaned from

history. With Tay-Sachs screening, a concerted effort was

made to educate community and religious leaders, who

then helped educate the public through outreach, mailings, media, and word of mouth before any screening took

place. Educational efforts were adjusted over time, and in

general, data indicate the majority of carriers believe they

were not stigmatized, although a small percentage of

noncarriers expressed attitudes of superiority (13,40),

Similarly, the Mediterranean ß-thalassemiaprograrn demonstrates the effectiveness of massive public education

through the local media, although some contend the

massive public education bordered on propaganda and

coercion (31). The sickle cell experience demonstrates

how poor public outreach and lack of knowledge among

professionals in the program lead to failure (54,66).

Regardless of the precise mechanism through which

education is achieved, implementation of CF carrier

screening can benefit from the knowledge that public

education has had a positive effect on previous screening

experiences. Lessons learned from Tay-Sachs, sickle cell,

and ß-thalassemia efforts can be applied to CF carrier

screening to increase public knowledge and decrease

stigmatization.

Counseling Carriers and At-Risk Couples

CF carrier screening can be informed by the Tay-Sachs,

sickle cell, and ß-thalassemia experiences with genetic

counseling. Lessons about informing patients, counseling

carriers, and counseling carrier couples can be applied to

CF carrier screening. The sickle cell experience often

omitted counseling, and so individuals with sickle cell

trait became anxious, not only because they were given

incorrect information, but also because they had received

inadequate counseling.

Tay-Sachs programs considered informed consent,

counseling of carriers, and counseling carrier couples to

be high priorities. Such informed consent and counseling

aided in the understanding and adjustment of individuals

“who were identified as carriers. In contrast, with no

apparent negative effect, ß-thalassemia carrier screening

in one pilot involving pregnant women was done on every

blood sample drawn, with no separate informed consent

(since providers felt they had patients’ implicit consent

for relevant diagnostic blood tests) (74), As is acknowledged to be essential, carriers and carrier couples received

post-test counseling.
Appendix B---Case Studies of Other Carrier Screening Programs . 265

Box B-3—Fragile X Syndrome

Recent advances elucidating the genetics of fragile X syndrome will have a great impact on future applications

to screening. Fragile X syndrome is the most common form of inherited mental retardation. Its incidence is about

1 in 1,500 male and 1 in 2,500 female live births (58). It includes minor dysmorphic features such as an elongated

Face, large ears, prominent jaw, and macroorchidism (78). The genetics of this disorder are different from the

mtosomal recessive disorders of cystic fibrosis, Tay-Sachs disease, sickle cell anemia, and the thalassernias. Fragile

X syndrome is an X-linked disorder-the gene for the disorder lies on the X chromosome, one of the two sex

determining human chromosomes. (Females have two X chromosomes, while males have one X and one Y

chromosome.)

Initially described in 1969, fragile X syndrome derives its name from the tendency for the tip of the X

chromosome to break off or appear fragile (figure B-2) (49). Its mode of inheritance, however, is unlike other

X-linked disorders such as hemophilia—it is neither recessive nor dominant. Unaffected men and women can

transmit a fragile X chromosome without manifesting any symptoms of the syndrome or expressing the fragile site

cytogenetically. Such transmitters, or carriers, can have children or grandchildren with fragile X syndrome (104).

The mothers of all affected children are considered to be obligate carriers, and no affected offspring arise as a direct

result of a new mutation (85). Among females, about half of the obligate carriers do not express the fragile X

chromosome. About 50 percent of heterozygous females express the disorder to some extent, and 30 percent are

mentally retarded. Approximately 20 percent of males who inherit the gene from their mothers are unaffected

carriers. Furthermore, severity appears variable in different siblings even within the same family (58).

Physical signs of the disorder are neither specific nor constant, and generally appear after childhood, making

diagnosis difficult. In the past, diagnosis generally occurred only after the birth of a second affected male (89), and

involved expert, labor-intensive laboratory analysis (84). Once the X chromosome was shown to be fragile, linkage

analysis of other family members could be performed, with prenatal tests also possible (33,86),

In 1991, researchers elucidated the uninique inheritance of fragile X syndrome and developed a DNA probe to

detect the fragile X site (58,104). Reliable and specific detection of all male or female carriers of a fragile X site

is now possible (58,68). Similarly, prenatal analysis can be performed (58,68,90). Moreover, results from DNA

assays appear to correlate with disease severity, and so can be used to predict clinical outcome (58). Fragile X

syndrome will likely be one of the first disorders for which the primary diagnosis is based on the direct analysis

of a mutation at the DNA level (68,84)

The increased knowledge of the genetics of fragile X syndrome has applications to genetic screening. Most

families with fragile X syndrome are presently unknown, because routine screening of the entire developmentally

disabled population has not been practical and because fragile X syndrome historically has been poorly diagnosed

(89). Given the high sensitivity and specificity of the new fragile X assay—and the value of early diagnosis for

genetic counseling purposes-the next step to consider is selected population screening (18). Although such

screening would initially focus on developmentally disabled males and females, if the frequency of normal

transmitting males is as high as the frequency of affected males, as one hypothesis predicts, an argument can be made

for general population screening, as has been proposed in the United Kingdom (18).

With respect to genetic counseling needs for fragile X syndrome, one study examined interest in prenatal

diagnosis and attitudes towards termination of affected pregnancies (51). Surveyed prior to the advent of the DNA

assay, 81 percent of women said they would seek prenatal diagnosis, and 28 percent indicated they would terminate

an affected pregnancy. There was no significant difference in responses between women who had affected children

and those who did not. Issues the subjects considered most important for discussion with a genetic counselor

included the availability of treatment, risk for having an affected grandchild, and expectations for the future

functioning of children with fragile X syndrome (51).

SOURCE: Office of Technology Assessment, 1992.
266 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure B-2—Fragile X Chromosomes

The fragile X site appears as a break or separation at the distal

end of the long arm of X chromosomes (arrows). This

computer-enhanced photomicrograph shows a carrier female

(top) and an affected male (bottom),

SOURCE: The Denver Children’s Hospital, 1992.

1.

2.

APPENDIX B REFERENCES

Andermann, E., Scriver, C. R., Wolfe, L. S., et al.,

“Genetic Variants of Tay-Sachs Disease: TaySachs Disease and Sandhoff’s Disease in French

Canadians, Juvenile Tay-Sachs Disease in Ubanese

Canadians, and a Tay-Sachs Screening Program in

the French Canadian Population, ” Tay-Sachs Disease: Screening and Prevention, M.M. Kaback (cd.)

(New Yorlq NY: Alan R. Liss, Inc., 1977).

Angastiniotis, M., “Cyprus: Thalassaernia Prograrnme,” Luncet 336:1 19-1120, 1990.

3.

4.

5.

6<

7,

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Benkendorf, J. L., Georgetown University Medical

Center, Washington, DC, personal communication,

December 1991.

Bernhardt, B. A., “Population Screening for the

Cystic Fibrosis Gene,” New England Journal of

Medicine 324:61-62, 1991.

Boehm, C.D., Antonarakis, S.E., Phillips, J. A., et

al., “Prenatal Diagnosis Using DNA Polymorphisms: Report on 95 Pregnancies at Risk for

Sickle-Cell Disease or fLThalassemia,’ New England Journal of Medicine 308:1054-1058, 1983.

Bowman, J. E., Department of Pathology, University of Chicago, personal communication, April

1992.

Bowman, J. E., and Murray, R. F., Jr., Genetic

Variation and Disorders in Peoples of African

Origin (Baltimore, MD: The Johns Hopkins University Press, 1990).

Cai, S.-P., Chang, C. A., Zhang, J. Z., et al., “Rapid

Prenatal Diagnosis of ~-’llalassemia Using DNA

Amplification and Nonradioactive Probes, ” Blood

73:372-374, 1989.

Cao, A., Gossens, M., and Pirastu, M., “PThalassemia Mutations in Meditemmean Populations,’ British Journal of Haernatology 71:309-

312, 1989.

Cao, A., Rosatelli, C., Galanello, R., et al., “Prenatal Diagnosis of Inherited Hemoglobinopathies, ”

Indian Journal of Pediatrics 56:707-717, 1989.

Cao, A., Rosatelli, C., Galanello, R., et al., “The

Prevention of Thalassemia in Sardinia,” Clinical

Genetics 36:277-285, 1989.

Chan, V., Chan, TK., and Todd, D., “Thalassemia

Screening and Prenatal Diagnosis in Hong Kong,”

AmericanJournul ofHurnan Genetics 49(Supp.):79,

1991.

Childs, B., “The Personal Impact of Tay-Sachs

Carrier Screening,” Tay-Sachs Disease: Screening

and Prevention, M.M. Kaback (cd.) (lJew York

NY: Alan R. Liss, Inc., 1977).

Clarke, J.ll: “Screening for Carriers of Tay-Sachs

Disease: Two Approaches,” Canadian Medical

Association Journal 119:549-550, 1978.

Clarke, J.T., Skomorowski, M.A., and Zuker, S.,

“Tay-Sachs Disease Carrier Screening: Follow-Up

of a Case-Finding Approach,’ American Journal of

Medical Genetics 34:601-605, 1989.

Clew, C.L., and Scriver, C.R., “Knowledge and

Attitudes Toward Genetic Screening Among HighSchool Students: The Tay-Sachs Experience,’ PecL”-

atrics 59;86-91, 1977.

Clew, C.L., and Scriver, C.R., “The Adolescent

Copes With Genetic Screening: A Study of TaySachs Screening Among High-School Students,”

Tay-Sachs Disease: Screening and Prevention,
Appendix B-Case Studies of Other Carrier Screening Programs . 267

18.

19.

20.

21.

22.

23.

24,

25.

26.

27.

28.

29.

30.

M.M. Kaback, (cd.) (New York, NY: Alan R. Liss,

Inc., 1977).

Connor, J. M., ‘‘Cloning of the Gene for the Fragile

X Syndrome: Implications for the Clinical Geneticist, ’ Journal of Medical Genetics 28:811-813,

1991.

Desnick, R.J., and Goldberg, J. D., “Tay-Sachs

Disease: Prospects for Therapeutic Intervention, ”

Tay-Sachs Disease: Screening and Prevention,

M.M. Kaback (cd.) (New York NY: Alan R. Liss,

Inc., 1977),

Drugan, A., Greb, A., Johnson, M, P., et al., ‘‘Determinants of Parental Decisions to Abort for Chromosome Abnormalities,” Prenatal Diagnosis 10:483-

490, 1990.

Dumars, K., MediGene Facility, Inc., Fountain

Valley, CA, personal communication, May 1992.

Faden, R.R., Chwalow, A. J., Quaid, K., et al.,

“Prenatal Screening and Pregnant Women’s Attitudes Toward the Abortion of Defective Fetuses, ”

American Journal of Public Health 77;288-290,

1987.

Fine, B. A,, Northwestern University Medical

School, Chicago, IL, personal communication, September 1991.

Fisher, L., Rowley, P.T., and Lipkin, M., Jr,,

“Genetic Counseling for &Thalassemia Trait Following Health Screening in a Health Maintenance

Organization: Comparison of Programmed and

Conventional Counseling,” American Journal of

Human Genetics 33:987-994, 1981.

Githens, J. H., Lane, P. A., McCurdy, R. S., et al.,

“Newborn Screening for Hemoglobinopathies in

Colorado: The First 10 Years,” American Journal

of Diseases of Children 144:466-470, 1990.

Golbus, M. S., Loughman, W. D., Epstein, C. J,, et al.,

‘‘Prenatal Diagnosis in 3,000 Amniocenteses,”

New England Journal of Medicine 300:157-163,

1979.

Goodman, M, J., and Goodman, L. E., ‘The Overselling of Genetic Anxiety,’ The Hastings Center

Report 12:20-27, 1982.

Grebner, E. E., and Tomczak, J., “Distribution of

Three et-Chain ~-Hexosaminidase A Mutations

Among Tay-Sachs Carriers,’ American Journal of

Human Genetics 48:604-607, 1991.

Hechtman, P., Kaplan, F., BayerIan, J., et al., ‘More

Than One Mutant Allele Cause Infantile Tay-Sachs

Disease in French Canadians, ” American Journal

of Human Genetics 47:815-822, 1990.

Hohzman, N. A., Proceed With Caution: Predicting

Genetic Risks in the Recombinant DNA Era (Baltimore, MD: The Johns Hopkins University Press,

1989).

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

Holtzman, N. A., Johns Hopkins University Hospital, Baltimore, MD, personal communication, December 19914

Hubbard, R., and Henifin, M. S., “Genetic Screening of Prospective Parents and of Workers: Some

Scientific and Social Issues,’ International Journal

of Health Services 15:231-251, 1985.

Jenkins, E. C., Krawczun, M. S., Stark-Houck, S.L.,

et al., “Improved Prenatal Detection of fra(x)

(q27.3): Methods for Prevention of False Negatives

in Chorionic Villus and Amniotic Fluid Cell Cultures, American Journal of Medical Genetics

38:447452, 1991.

Kaback, M. M., Nathan, TJ., and Greenwald, S.,

“Tay-Sachs Disease: Heterozygote Screening and

Prenatal Diagnosis—U.S. Experience and World

Perspective,’ Tay-Sachs Disease: Screening and

Prevention, M.M. Kaback (cd.) (New York, NY:

Alan R. Liss, Inc., 1977).

Kaback, M. M., Zeiger, R. S., Reynolds, L. W., et al,,

“Approaches to the Control and Prevention of

Tay-Sachs Disease,’ Progress in Medical Genetics

10:103-134, 1974.

Kark, J. A,, Posey, D. M., Schumacher, H. R., et al.,

“Sickle-Cell Trait as a Risk Factor for Sudden

Death in Physical Training,’ New England Journal

of Medicine 317:781-787, 1987.

Kazazian, H. H., “Molecular Pathology of the ~-

Globin Gene Cluster,” Trends in Neuroscience

8:192-200, 1985.

Kazazian, H. H., “Thalassemia Syndrome: Molecular Basis and Prenatal Diagnosis in 1990,” Seminars in Hematology 27:209-228, 1990.

Kazazian, H. H., Johns Hopkins University School

of Medicine, Baltimore, MD, personal communication, December 1991.

Kenen, R.H., and Schmidt, R. M., “Stigmatization

of Carrier Status: Social Implications of Heterozy -

gote Genetic Screening Programs,’ American Journal of Public Health 68:1 16-1120, 1978.

Kovner, A., The National Tay-Sachs and Allied

Diseases Association, Inc., Brookline, MA, personal communication, August 1991.

Kuliev, A. M., ‘‘The WHO Control Program for

Hereditary Anemias,’ Birth Defects: Original Article Series 23(5 B):383-394, March of Dimes Birth

Defects Foundation, 1988.

LAw, R. V., Cunningham, G., Simons, M. J., et al.,

“Defining DNA Diagnostic Tests Appropriate for

Standard Clinical Care,” American JourM~ of

Human Genetics 47:583-590, 1990.

Isbo, R. V., Saiki, R. K., Swanson, K., et al.,

“Prenatal Diagnosis of cx-l%alassemia by Polymerase Chain Reaction and Dual Restriction Enzyme Analysis,” Human Genetics 85:293-299,

1990.
268 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

IAkowitz, S., Chevra Dor Yeshorim, Center for the

Prevention of Jewish Genetic Diseases, Brooklyn,

NY, personal communication, March 1992,

Imukopoulos, D., “Screening for Thalassemia and

HbS in the East Mediterranean,’ American Journal

of Human Genetics 49(Supp.):79, 1991.

Imwden, J. A., “Role of the Physician in Screening

for Carriers of Tay-Sachs Disease,” Canadian

Medicai Association Journal 119:575-578, 1978.

I.mwden, J. A., and Davidson, J., ‘‘Tay-Sachs Screening and Prevention: The Canadian Experience, ”

Tay-Sachs Disease: Screening and Prevention,

M.M. Kaback (cd.) (New Yorlq NY: Alan R. Liss,

Inc., 1977).

Lubs, H. A., “A Marker X Syndrome, ” American

Journal of Human Genetics 21:231-244, 1969.

McDowell, G. A., Schultz, R. A., Schwartz, S,, et al,,

“Presence of Both Ashkenazic Tay-Sachs Mutations in a Non-Jewish Inbred Population, ” American Journal of Human Genetics 45( Supp.):A9,

1989.

Meryash, D.L., and Abuelo, D., ‘Counseling Needs

and Attitudes Toward Prenatal Diagnosis and Abortion in Fragile X Families, ” Clinical Genetics

33:349-355, 1988.

Merz, B., “Matchmaking Scheme Solves TaySachs Problem,’ Journul of the American Medical

Association 258:2636-2639, 1987.

Modell, B., and Petrou, M., “Review of Control

Programs and Future Trends in the United Kingdom,” Birth Defects: Original Article Series 23(5 B):

433-442, March of Dimes Birth Defects Foundation, 1988.

National Research Council, Committee for the

Study of Inborn Errors of Metabolism, Genetic

Screening: Programs, Principles, and Research

(Washington, DC: National Academy of Sciences,

1975).

National Tay-Sachs and Allied Disease Association, Tay Sachs and the Allied Diseases: What Every

Family Should Know, brochure, 1987.

Navon, R., and Proia, R.L., “Tay-Sachs Disease in

Moroccan Jews: Deletion of a Phenylalanine in the

a-Subunit of cx-Hexosaminidase, American Journal of Human Genetics 48:412-419, 1991.

Nora, J, J., and Fraser, F. C., Medical Genetics:

Principles and Practice (Philadelphia, PA: ha &

Febiger, 1989),

Oberle, I., Rousseau, F., Heitz, D., et al., “Instability of a 550-Base Pair DNA Segment Abnormal

Methylation in Fragile X Syndrome, ” Science

252:1097-1102, 1991.

O’Brien, J. S., Okada, S., Chen, A., et al., “TaySachs Disease: Detection of Hetero~gotes and

Homozygotes by Serum Hexosarninidase Assay,”

New EnglandJournal ofMedicine 283: 15-20,1970.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70,

71.

72.

73.

Okada, S., and O’Brien, J. S., “Tay-Sachs Disease:

Generalized Absence of a ~-D-N-acetylhexosaminidase Component,” Science 165:698-700, 1969.

Orkin, S.H., Little, P.F., Kazazian, H.H., et al.,

“Improved Detection of the Sickle Mutation by

DNA Analysis,’ New England Journal ofMedicine

307:32-36, 1982.

Paw, B. H,, Tieu, P. T., Kabac~ M. M., et al.,

‘‘Frequency of Three Hex A Mutant Alleles among

Jewish and Non-Jewish Carriers Identified in a

Tay-Sachs Screening Program,’ American Journal

of Human Genetics 47:698-705, 1990.

Potter, J. L., and Robinson, H. B., Jr., “Screening for

the Tay-Sachs Carrier: A Compromise Program, ”

Clinical Chemistq 27:523-525, 1981.

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and Behavioral Research, Screening and Counseling for

Genetic Conditions: A Report on the Ethical,

Social, and Legal Implications of Genetic Screening, Counseling, and Education Programs (Washington, DC: U.S. Government Printing Office,

1983).

Reilly, P., Genetics, L.uw and Social Policy (Cambridge, MA: Harvard University Press, 1977).

Roberts, L., “One Worked: The Other Didn’t

(Genetic Screening programs for Tay-Sachs and

Sickle Cell Anemia),” Science 247:18, 1990.

Rosner, F., “ConfidentialTay-Sachs Carrier Screening,” New York State Journal of Medicine 89:585,

1989.

Rousseau, F., Heitz, D,, Biancakma, V., et al.,

‘‘Direct Diagnosis by DNA Analysis of the Fragile

X Syndrome of Mental Retardation,’ New England

Journal of Medicine 325:1673-1681, 1991.

Rowley, P.T, ‘‘Prenatal Screening for Hemoglobinopathies,” American Journal of Human Genetics

49:466467, 1991.

Rowley, P.11, Fisher, L., and Lipkin, M., Jr.,

“Screening and Genetic Counseling for ~-

Thalassemia Trait in a Population Unselected for

Interest: Effects on Knowledge and Mood,” American Journal of Human Genetics 31:718-730, 1979.

Rowley, P.T, Lipkin, M., Jr., and Fisher, L.,

“Screening and Genetic Counseling for BetaThalassemia Trait in a Population Unselected for

Interest: Comparison of Three Counseling Methods,” American Journal of Human Genetics 36:677-

689, 1984.

Rowley, P.T., Imader, S., Sutera, C. J., et al.,

‘‘prenatal Hemoglobinopathy Screening: Receptivity of Southeast Asian Refugees, ’ American Journal of Preventive Medicine 3:317-322, 1987.

Rowley, P.’I’l, Loader, S., Sutera, C.J., et al., “Do

Pregnant Women Benefit From Hemoglobinopathy
Appendix B-Case Studies of Other Carrier Screening Programs ● 269

74.

75.

76.

77.

78.

79.

80,

81.

82.

83.

84.

85.

86.

87.

Screening?,” Annals of the New York Acaakmy of

Sciences 565:152-160, 1989.

Rowley, P.T, Loader, S., Sutera, C. J., et al.,

‘‘Prenatal Screening for Hemoglobinopathies. I. A

Prospective Regional Trial,’ American Journal of

Human Genetics 48:439446, 1991.

Rowley, P.T., Loader, S., and Walden, M., “Toward Providing Parents the Option of Avoiding the

Birth of the First Child With Cooley’s Anemia:

Response to Hemoglobinopathy Screening and

Counseling During Pregnancy,’ Annals of the New

York Academy of Sciences 445:408416, 1985.

Saiki, R. K., Chang, C.-A., bvenson, C. H., et al.,

“Diagnosis of Sickle Cell and ~-Thalassemia With

Enzymatically Amplified DNA and Nonradioactive

Allele-Specific Oligonucleotide Probes,’ New England .lourna[ of Medicine 319:537-541, 1988.

Sandhoff, K,, Conzelmann, E., Neufeld, E. F,, et al.,

‘‘The G~L Gangliosidoses” The Metabolic Basis of

Inherited Disease, C.R. Scriver, A.L. Beaudet, W,S,

Sly, et al. (eds.) (New York, NY: McGraw Hill,

1989).

Schepis, C., Palazzo, R., Ragusa, R. M., et al.,

‘ ‘Association of Cutis Verticis Gyrata With Fragile

X Syndrome and Fragility of Chromosome 12,”

Lancet 2:279, 1989.

Schneck, L., Friedland, J., Valenti, C., et al.,

“Prenatal Diagnosis of Tay-Sachs Disease, ” Lancet 1:582-583, 1970.

Schulrnan, J. D., Genetics & IVF Institute, Fairfax,

VA, personal communication, December, 1991.

Scriver, C. R,, Bardanis, M., Cartier, L., et al.,

“&ThalassemiaDisease Prevention: Genetic Medicine Applied, ’ American Journal of Human Genetics 36: 1024-1038, 1984.

Scriver, C. R., and Clew, C. L., “Carrier Screening

for Tay-Sachs Disease, ” Luncet 335:856, 1990.

Scriver, C, R., and Clew, C. L., “Carrier Screening

for Tay-Sachs Disease, ” Lancet 336:191, 1990.

Shapiro, L. R., “The Fragile X Syndrome: A PecuIim Pattern of Inheritance, ” New England Journal

of Medicine 325: 1736-1738, 1991.

Shapiro, L. R., Wilmot, P. L., and Murphy, P.D.,

‘‘Prenatal Diagnosis of the Fragile X Syndrome:

Possible End of the Experimental Phase for Amniotic Fluid, ’ American Journal of Medical Genetics

38:453-455, 1991.

Shapiro, L. R., Wilmot, P. R., Shapiro, D. A., et al.,

“Cytogenetic Diagnosis of the Fragile X Syndrome: Efficiency, Utilization, and Trends, ’ American Journal of Medical Genetics 38:408410,

1991.

Steinberg, M. H., and Embury, S. H., ‘ ‘~-

Thalassemia in Blacks: Interactions With the Sickle

88.

89,

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

Hemoglobin Gene,” Birth Defects: Original Article

Series 23 (5A):43-48, March of Dimes Birth

Defects Foundation, 1988.

Sullivan, L. W., “Risks of Sickle-Cell Trait: Caution and Common Sense,’ New England Journal of

Medicine 317:830-831, 1987.

Sutherland, G. R., ‘Fragile Sites on Human Chromosomes: Demonstration of Their Dependence on the

~pe of Tissue Culture Medium,” Science 197:25-

26, 1977.

Sutherland, G. R., Gedeon, A., Kornman, L., et al.,

“Prenatal Diagnosis of Fragile X Syndrome by

Direct Detection of the Unstable DNA Sequence,”

New England Journal of Medicine 325; 1720-1721,

1991.

ten Kate, L. P., and Tijmstra, T., ‘‘Carrier Screening

for Tay-Sachs Disease and Cystic Fibrosis,’ Lancet

336:1527-1528, 1990.

Thompson, J. S., and Thompson, M. W., Genetics in

Medicine (Philadelphia, PA: W.B. Saunders Co.,

1980).

Twci, P. M., “Seven Years Experience With Tay -

Sachs Screening in Florida,’ Journal of the Floriaiz

Medical Association 68:24-29, 1981.

Triggs-Raine, B. L., Feigenbaum, A. S. J., Natowicz,

M., et al., “Screening for Carriers of Tay-Sachs

Disease Among Ashkenazic Jews: A Comparison of

DNA-Based and Enzyme-Based Tests,’ New England Journal of Medicine 323:6-12, 1990.

Tymstra, T., “Prenatal Diagnosis, Prenatal Screening, and the Rise of the Tentative Pregnancy, ”

International Journal of Technology Assessment in

Health Care 7:509-516, 1991.

Valverde, K. D., Cystic Fibrosis Center, St. Vincent Hospital and Medical Center, New York, NY,

personal communication, December 1991.

Vecht, J., Zeigler, M., Segal, M., et al., “Tay-Sachs

Disease Among Moroccan Jews,’ Israel Journal of

Medical Science 19:67-69, 1983.

Wang, S., Wang, L., and Zhang, B., “A Survey of

Hb Bart in Cord Blood and the ct-Globin Gene in

South China,” Birth Defects: Original Article

Series 23 (5 A):23-30, March of Dimes Birth Defects Foundation, 1988.

Watson, E. K., Mayall, E., Chapple, J., et al.,

‘‘Screening for Carriers of Cystic Fibrosis Through

Primary Health Care Services,” British Medical

Journal 303:504-507, 1991.

Weatherall, D. J., “The Evolution of Thalassemia

Screening, ’ American Journal of Human Genetics

49(supp.):79, 1991.

Weatherall, D. J., Clegg, J. B., Higgs, D. R., et al.,

“The Hemoglobinopathies,” The Metabolic Basis
270 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

of Inherited Disease, C.R. Scriver, A.L. Beaudet,

W.S. Sly, et al. (eds.) (New York, NY: McGraw

Hill, 1989).

102. Wilfond, B., University of Wisconsin Medical

School, Madison, WI, personal communication,

December 1991.

103. Willey, A. M., New York State Department of

Health, Albany, NY, personal communications,

January 1992, May 1992.

104. Yu, S., Pritchard, M., Kremer, E., et al., “Fragile X

Genotype Characterized by an Unstable Region of

DNA,” Science 252:1179-1181, 1991.

105. Yuen, J., and Hsia, YE., “Consumer Attitudes

Toward Thalassemia Screening: Heterozygotes of

Multi-Ethnic Origin,” American Journal of Human

Genetics 49( Supp.):331, 1991.

106. Zeesman, S., Clew, C.L., Cartier, L., et al., “A

Private View of Heterozygosity: Eight-Year FollowUp Study on Carriers of the Tay-Sachs Gene

Detected by High School Screening in Montreal,”

American Journal of Medical Genetics 18:769-778,

1984.

107. Zhang, J, Z., Cai, S. P,, and Kan, Y. W., “Thalassemia Screening and Prenatal Diagnosis in South

China,” American Journal of Human Genetics

49(Supp.):80, 1991.
Appendix C

Acknowledgments

OTA would like to thank the members of the advisory panel who commented on drafts of this report, the contractors

who provided material for this assessment, and the many individuals and organizations that supplied information for the

study. In addition, OTA acknowledges the following individuals for their review of drafts of this report:

Naomi Aronson

Blue Cross and Blue Shield Association

Chicago, IL

Lori B. Andrews

American Bar Foundation

Chicago, IL

George J. Annas

Boston University School of Public Health

Boston, MA

Adrienne Asch

New York, NY

Sema K. Aydede

Istanbul, Turkey

Raj Barathur

Specialty Laboratories

Santa Monica, CA

Jonathan Beckwith

Harvard Medical School

Boston, MA

Michael Begleiter

Children’s Mercy Hospital

Kansas City, MO

Clyde J. Behney

Health Program

Office of Technology Assessment

Judith Benkendorf

Georgetown University Medical Center

Washington, DC

David P. Bick

Genetics & IVF Institute

Fairfax, VA

Rob Bier

American Council of Life Insurance

Washington, DC

Barbara Bowles-Biesecker

University of Michigan Medical Center

Ann Arbor, MI

Paul R. Billings

California Pacific Medical Center

San Francisco, CA

Frank Blanchard

Howard Hughes Medical Institute

Bethesda, MD

Thomas F. Boat

University of North Carolina at Chapel Hill

Chapel Hill, NC

Mary Anne Bobinski

University of Houston Law Center

Houston, TX

Martin Bobrow

United Medical and Dental Schools of Guy’s

and St. Thomas’s Hospital

London, England

James E. Bowman

University of Chicago

Chicago, IL

David J.H. Brock

Western General Hospital

Edinburgh, Scotland

Keith Brown

GeneScreen, Inc.

Dallas, TX

Tony J. Beugelsdijk

Los Alarnos National Laboratory

Los Alamos, NM

Peter Carpenter

Stanford University Center for Bioethics

Atherton, CA

Aravinda Chakravarti

University of Pittsburgh

Pittsburgh, PA

Gary Claxton

National Association of Insurance Commissioners

Washington, DC

Ellen Wright Clayton

The Vanderbilt Clinic

Nashville, TN

Francis S. Collins

Howard Hughes Medical Institute

Ann Arbor, MI

–271–
272 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

P. Michael Conneally

Indiana University School of Medicine

Indianapolis, IN

Elizabeth A. Conway

Blue Cross and Blue Shield Association

Washington, DC

James Corbett

MIB, Inc.

Westwood, MA

Virginia Corson

Johns Hopkins University Hospital

Baltimore, MD

Robert M. Cook-Deegan

Institute of Medicine

Washington, DC

George Cunning harn

California Department of Health Services

Berkeley, CA

Peter T. D’Ascoli

St. Paul Ramsey Medical Center

St. Paul, MN

Neil Day

MIB, Inc.

Westwood, MA

Robert J. Desnick

Mt. Sinai School of Medicine

New York NY

Daniel W. Drell

U.S. Department of Energy

Germantown, MD

Sherman Elias

University of Temessee School of Medicine

Memphis, TN

C.M. Eng

Mt. Sinai School of Medicine

New York, NY

Mark Evans

American Medical Association

Chicago, IL

Lee Fallen

Genetics & IVF Institute

Fairfax, VA

Susan Dee Fernbach

Baylor College of Medicine

Houston, TX

Norman Fost

University of Wisconsin School of Medicine

Madison, WI

Michelle Fox

UCLA Medical Center

Los Angeles, CA

Robert Funk

GeneScreen, Inc.

Dallas, TX

Barry R. Furrow

Widener University School of Law

Wilmington, DE

Alan Garber

National Bureau of Economic Research, Inc.

Stanford, CA

Fred Gilbert

Cornell University Medical College

New York, NY

Robert C. Giles

GeneScreen, Inc.

Dallas, TX

Frank Greenberg

Institute for Molecular Genetics

Houston, TX

Gayle Greenberg

Cystic Fibrosis Foundation-Metropolitan

Washington, DC Chapter

Bethesda, MD

Robert M. Greenstein

University of Connecticut Health Center

Farmington, CT

Wayne W. Grody

UCLA School of Medicine

Los Angeles, CA

Joseph L. Hackett

U.S. Food and Drug Administration

Rockville, MD

Mark Hall

Arizona State University College of Law

Tempe, AZ

Barbara Handelin

IG Laboratories, Inc.

Framingham, MA

Peter S. Harper

University of Wales College of Medicine

Cardiff, Wales

Kiki Hellman

U.S. Food and Drug Administration

Rockville, MD

Patricia J. Hoben

Howard Hughes Medical Institute

Bethesda, MD
Appendix C---Acknowledgments ● 273

Neil A. Holtzman

Johns Hopkins University Hospital

Baltimore, MD

Frits A. Hommes

Medical College of Georgia

Augusta, GA

Juli A. Horwitz

Vivigen

Santa Fe, NM

Lauren S. Jenkins

Kaiser Permanence

San Jose, CA

James H. Jett

Las Alamos National Laboratory

Los Alamos, NM

Shirley Jones

Genetics & IVF Institute

Fairfax, VA

Eric T. Juengst

National Center for Human Genome Research

Bethesda, MD

Michael M. Kaback

University of California,

San Diego Medical Center

San Diego, CA

Deborah Kaplan

World Institute on Disability

Oakland, CA

Gail C. Kaplan

Vivigen

Santa Fe, NM

Nancy E. Kass

Johns Hopkins University

Baltimore, MD

Haig H. Kazazian, Jr.

Johns Hopkins University Hospital

Baltimore, MD

Bartha Maria Knoppers

University of Montreal Faculty of Law

Montreal, Canada

Michael R. Knowles

University of North Carolina at Chapel Hill

Chapel Hill, NC

Elinor Langfelder

National Center for Human Genome Research

Bethesda, MD

Jane S. Lin-Fu

Maternal and Child Health Bureau

Rockville, MD

Walter B. Maher

Chrysler Corp.

Washington, DC

Babetta L. Marrone

Los Alamos National Laboratory

Los Alamos, NM

Karla J. Matteson

University of Tennessee Medical Center-Knoxville

Knoxville, TN

F. John Meaney

Scottsdale, AZ

Abbey S. Meyers

National Organization for Rare Disorders

New Fairfield, CT

Amo S. Motulsky

University of Washington

Seattle, WA

Patricia D. Murphy

New York State Department of Health

Albany, NY

Thomas H. Murray

Case Western Reserve University

Cleveland, OH

Frank Nardi

MIB, Inc.

Westwood, MA

David M. Orenstein

children’s Hospital of Pittsburgh

Cystic Fibrosis Center

Pittsburgh, PA

David Orentlicher

American Medical Association

Chicago, IL

Jude C. Payne

Health Insurance Association of America

Washington, DC

Vidois M. Pearce

Financial Concepts, Inc.

Santa Fe, NM

L.C. Pham ‘

Roche Biomedical Laboratories

Research Triangle Park, NC

Robert J. Pokorski

North American Reassurance Co.

Westport, CT

Martin Pollard

Lawrence Berkeley Laboratory

Berkeley, CA
274 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Stirling M. Puck

Vivigen

Santa Fe, NM

Kimberly A. Quaid

Indiana University School of Medicine

Indianapolis, IN

Harvie E. Raymond

Health Insurance Association of America

Washington, DC

C. Sue Richards

GeneScreen, Inc.

Dallas, TX

John Robertson

University of Texas School of Law

Austin, TX

Martin Rose

Genentech, Inc.

Washington, DC

Karen Rothenberg

University of Maryland School of Law

Baltimore, MD

Mark A. Rothstein

University of Houston Law Center

Houston, TX

Peter T. Rowley

University of Rochester Medical Center

Rochester, NY

Suzie Rubin

Biological Applications Program

Office of Technology Assessment

Marianne Schwartz

Rigshospitalet

Copenhagen, Denmark

Charles R. Scriver

McGill University

Montreal, Canada

Burton L. Shapiro

University of Minnesota Health Science Center

Minneapolis, MN

Ann C.M. Smith

Reston, VA

Bonnie Steinbeck

University of Albany

Albany, NY

Edward Theil

Lawrence Berkeley Laboratory

Berkeley, CA

Helen Travers

IG Laboratories, Inc.

Miami, FL

Lap-Chee Tsui

Hospital for Sick Children

Toronto, Canada

Donald C. Uber

Lawrence Berkeley Laboratory

Berkeley, CA

Kathleen D. Vidverde

St. Vincent’s Hospital Cystic Fibrosis Center

New York, NY

Madge Vickers

Medical Research Council

London, England

Martha Volner

Alliance of Genetic Support Groups

Washington, DC

Judith L. Wagner

Health Program

Office of Technology Assessment

Ernestyne H. Watkins

National Institutes of Health

Bethesda, MD

Dorothy C. Wertz

Shriver Center for Mental Retardation, Inc.

Waltham, MA

Joan Weiss

Alliance of Genetic Support Groups

Washington, DC

Nancy S. Wexler

Hereditary Disease Foundation

Santa Monica, CA

Benjamin Wilfond

Arizona Health Sciences Center

Tucson, AZ

Robert Williamson

St. Mary’s Hospital Medical School

London, England

Ann Willey

New York State Department of Health

Albany, NY

David R. Witt

Kaiser Permanence

San Jose, CA
Appendix D

List of Contractor Documents

For this assessment, OTA commissioned reports on various topics relevant to carrier screening for cystic fibrosis. The

manuscripts of six of these contractors are available in a single volume (NTIS# PB 92-183 185) from the National

Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161; (703) 487-4650.

Adrienne Asch, New York, NY, “Carrier Screening, Cystic Fibrosis, and Stigma. ”

Jeffrey L. Fox, Washington, DC, “Cystic Fibrosis, Genetic Screening, and Insurance: Summary of OTA Workshop

Proceedings, February 1, 1991, ”

F. John Meaney, Scottsdale, AZ, “CORN Report on Funding of State Genetic Services Programs in the United States,

1990. ”

Thomas H, Murray, Center for Biomedical Ethics, Case Western Reserve University, Cleveland, OH, “Genetics, Ethics,

and Health Insurance. ’

Mark V. Pauly, Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA, “The

Cost-Effectiveness of Population Carrier Screening for Cystic Fibrosis: Draft Final Report;” ‘‘The CostEffectiveness of Population Carrier Screening for Cystic Fibrosis: Final Report;” “The Cost-Effectiveness of

Population Carrier Screening for Cystic Fibrosis: Appendix to Final Report. ”

Bonnie Steinbeck, University of Albany, Albany, NY, ‘‘Ethical Implications of Population Screening for Cystic Fibrosis:

The Concept of Harm and Claims of Wrongful Life.

–275-
Appendix E

List of Workshops and Participants

Cystic Fibrosis, Genetic Screening, and Insurance

February 1, 1991

Norman Fost, Workshop Chair

University of Wisconsin School of Medicine

Madison, WI

Rob Bier

American Council of Life Insurance

Washington, DC

Elizabeth A. Conway

Blue Cross and Blue Shield Association

Washington, DC

Barry R. Furrow

Widener University School of Law

Wilmington, DE

Robert M. Greenstein

University of Connecticut Health Center

Farmington, CT

Dennis Hodges

Group Health Association of America

Washington, DC

Nancy Kass

Johns Hopkins University

Baltimore, MD

Angkle Khachadour

Hastings College of the Law

San Francisco, CA

Cystic Fibrosis, Genetic Tests, and Self-Insurance Under ERISA

August 6, 1991

AngUe Khachadour, Workshop Chair

Hastings College of the Law

San Francisco, CA

Walter B. Maher

Chrysler Corp.

Washington, DC

Jude C. Payne

Health Insurance Association of America

Washington, DC

Robert J. Pokorski

North American Reassurance Co.

Westport, CT

Contractors:

John M. Boyle

Schulman, Ronca, & Bucuvalas, Inc.

Silver Spring, MD

R. Alta Charo

University of Wisconsin Law School

Madison, WI

Sonia Muchnik

Washington Business Group on Health

Washington, DC

Nancy Kass

Johns Hopkins University

Baltimore, MD

Ann Burden

Genetics & IVF Institute

Fairfax, VA

Mark A. Rothstein

University of Houston Law Center

Houston, TX

Gary Claxton

National Association of Insurance Commissioners

Washington, DC

Valois M. Pearce

Financial Concepts, Inc.

Santa Fe, NM

Mary Anne Bobinski

University of Houston Law Center

Houston, TX

Deborah Chollet

Georgia State University

Atlanta, GA

-27 6
Appendix F

Acronyms and Glossary

Acronyms

-/- -negative CF carrier/negative CF carrier

(couple)

+/- —positive CF carrier/negative CF carrier

(couple)

+/+ —positive CF carrier/positive CF carrier

(couple)

621 +1 G---›T—a CF mutation

A

ABMG

ACOG

ADA

AHCPR

AIDs

APKD

ARMs

ASHG

ASO

ATP

BABI

Bart’s

BC/BS

c

Ca

2+

CAMP

CAP

CDHS

CF

CF Trust

CFF

CFR

CFTRr

—adenine

—American Academy of Pediatrics

—American Board of Medical Genetics

—American College of Obstetricians and

Gynecologists

—Americans With Disabilities Act of

1990

—alpha-fetoprotein

—Agency for Health Care Policy and

Research

—acquired immunodeficiency syndrome

—American Medical Association

—adenosine rnonophosphate

—adult polycystic kidney disease

—arnpliflcation refractory mutation system

—American Society of Human Genetics

—allele-specific oligonucleotide

—adenosine triphosphate

-blastomere analysis before implantation

-St. Bartholomew’s Hospital (London)

—Blue Cross and Blue Shield

-cytosine

-calcium ion

-cyclic adenosine monophosphate

--College of American Pathologists

-California Department of Health Services

-cystic fibrosis

-Cystic Fibrosis Research Trust (United

Kingdom)

---Cystic Fibrosis Foundation

-Code of Federal Regulations

-cystic fibrosis transmembrane conductance regulator

CHAMPUS -Civilian Health and Medical Program of

the Uniformed Services

Cl- -chloride ion

CLIA -Clinical Laboratory Improvement Amendments of 1988

CORN -Council of Regional Networks for Genetic Services

CVS --chononic villus sampling

DF508 -delta F508 (most prevalent CF mutation)

DF508+6-12-delta F508 plus six to 12 additional CF

D1507

DHHS

DNA

DNase

DOD

DOE

EEOC

ELSI

ERXSA

FCC

FDA

FFDCA

FR

G

G542X

G551D

GAO

GI

GP

Hb

HCFA

HexA

HHMI

HMO

HSRC

HSRP

HUGA-1

IDE

IRT

I v

kb

L

LCR

MCH

MCV

MDA

MDR

mutations

—a CF mutation

—U.S. Department of Health and Human

Services

-deoxyribonucleic acid

-deoxyribonuclease

—US. Department of Defense

—U.S. Department of Energy

—U.S. Equal Employment Opportunity

Commission

—Ethical, Legal, and Social Issues Programs (NIH or DOE)

—Employee Retirement income Security

Act of 1974

—Federal Communications Commission

—U.S. Food and Drug Administration

—Federal Food, Drug, and Cosmetic Act

of 1938

—Federal Register

—guanine

—a CF mutation

—a CF mutation

--General Accounting Office

—gastrointestinal

—general practitioner (United Kingdom)

-hemoglobin

—Health Care Financing Administration

-hexosaminadase A

—Howard Hughes Medical Institute

—Health Insurance Association of

America

—health maintenance organization

—Health Services Research Committee

(MRC; United Kingdom)

—Health Services Research Panel (MRC;

United Kingdom)

—Human Genome Analysis System (Japan)

—Investigational Device Exemption

—immunoreactive trypsin

—intravenous

—kilobase(s); 1,000 base pairs

—liter

—ligase chain reaction

—Maternal and Child Health (Federal

block grant)

—mean corpuscular volume

—Medical Device Amendments of 1976

—medical devices reporting (1984 regulation)

–277-
278 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

—milligram

—Military Health Services System

—Medical Information Bureau, Inc.

—millimnole

—Medical Research Council (United Kingdom)

—messenger ribonucleic acid

—maternal serum alpha-fetoprotein

—a CF mutation

—sodium ion

—National Center for Human Genome

Research (NIH)

—National Heart, Lung, and Blood Institute (NIH)

—National Health Service (United Kingdom)

—National Institute of Child Health and

Human Development (NIH)

—National Institute of Diabetes and Digestive and Kidney Diseases (NIH)

—National Institutes of Health

—National Research Council

—National Science Foundation

—National Society of Genetic Counselors

-neural tube defect

—National Tay-Sachs and Allied Diseases

Association

-Office of Technology Assessment

—polymerase chain reaction

—premarketing approval application

—preferred provider organization

—physical therapy

—a CF mutation

—Recombinant DNA Advisory Committee

(NIH)

—request for applications

—restriction fragment length polymorphism

—ribonucleic acid

-Safe Medical Devices Act of 1990

-Special Projects of Regional and National Significance

-thymine

—University of California, Los Angeles

—a CF mutation

Glossary of Terms

Adverse selection: The tendency of persons with poorer

than average health expectations to apply for or

continue insurance to a greater extent than persons

with average or better health expectations. Also

known as “antiselection.”

Amino acid: Any of a group of 20 molecules that

combine to form proteins in living things. The

sequence of amino acids in a protein is determined

by the genetic code.

Amniocentesis: The most widely used technique of

prenatal diagnosis. Cells shed by the developing

fetus are extracted from a sample of amniotic fluid

withdrawn from the expectant mother’s uterus at

about 16 weeks of gestation by means of a

hypodermic needle. The cells are cultured and

then tested for chromosomal defects. In addition,

scientists can now analyze the DNA of these cells

directly, identifying specific genetic errors.

Allele: Alternative form of a genetic locus (e.g., at a locus

for eye color there might be alleles resulting in

blue or brown eyes); alleles are inherited separately from each parent.

Allele-specific oligonucleotide (ASO) probe: Probes

that are able to exactly match the nucleotide

sequence of a portion of a gene, detecting even

single-base differences.

Automation: Technology, such as robotics, developed to

increase the speed, volume, and accuracy of

routine DNA diagnostic procedures.

AutoradiogPam: An x-ray film image showing the

position of radioactive substances. Sometimes

called “autorad.”

Autoradiograph: See autoradiogram.

Autoradiography: A process for identifying radioactively labeled molecules or fragments of molecules.

Autosome: Chromosome not involved in sex determination. In a complete set of human chromosomes,

there are 44 autosomes (22 pairs).

Base pair: Two complementary nucleotides held together

by weak bonds. Two strands of DNA are held

together in the shape of a double helix by the

bonds between base pairs. The base adenine pairs

with thyrnine, and guanine pairs with cytosine.

ß-thalassemia: An autosomal recessive disorder affecting the red blood cells, resulting in anemia,

infections, growth retardation, andothercomplications. ß-thalassemia predominantly occurs among

individuals of Mediterranean, Middle Eastern,

Asian Indian, Chinese, Southeast Asian, and

African descent.

Blot: See Southern blot.

Buccal: Relating to the inside of the cheek. A buccal swab

collects cells from the inside of the cheek for CF

mutation analysis.

Carrier: An individual apparently normal, but possessing a single copy of a recessive gene obscured

by a dominant allele; a heterozygote.

Cell: The smallest component of life capable of independent reproduction and from which DNA can be

isolated.
Appendix F---Acronyms and Glossary ● 279

Chest physical therapy (chest PT): A cornerstone of CF

therapy that moves the mucus blocking major air

passages out of the lungs. One form of chest PT is

bronchial drainage, during which an individual

claps on the chest or back of the patient who is

usually lying on a table or over a couch, to loosen

mucus that the patient coughs up.

Chorionic villus sampling (CVS): A method of prenatal

diagnosis undertaken as early as the 9th week of

pregnancy. Fetal cells from chorionic villi (protrusions of a membrane, called the chorion, that

surround a fetus during early development) are

suctioned out through the uterus and their DNA is

analyzed.

Chromosomal aberration: An abnormal chromosomal

complement resulting from the loss, duplication,

or rearrangement of genetic material.

Chromosome: A threadlike structure that carries genetic

information arranged in a linear sequence. In

humans, it consists of a complex of nucleic acids

and proteins.

Cloning: The process of asexually producing a group of

cells (clones), all genetically identical to the

original ancestor. In recombinant DNA technology, the process of using a variety of DNA

techniques to produce multiple copies of a single

gene or segment of DNA.

Community rating: A method of determining premium

rates based on the allocation of total costs without

regard to past group experience, Community

rating is required of federally qualified health

maintenance organizations.

Complementary DNA (cDNA): DNA synthesized from

a messenger RNA template; the single-strand

form is often used as a probe in physical mapping.

Confidentiality: A fundamental component of the health

care provider-patient relationship in which the

professional has the duty to keep private all that is

disclosed by the patient.

Consanguineous: Related by blood or origin, rather than

Cystic

Cystic

by marriage.

fibrosis (CF): A life-shortening, autosomal recessive disorder affecting the respiratory, gastrointestinal, reproductive, and skeletal systems, as

well as the sweat glands. CF is caused by

mutations in the CF gene that affect the gene

product, cystic fibrosis transmembrane conductance regulator. Individuals with CF possess two

mutant CF genes.

fibrosis carrier: An individual who possesses one

CF mutation and one normal CF gene. CF carriers

manifest no symptoms of the disorder. See carrier.

Cystic fibrosis carrier screening: The performance of

tests on persons for whom no family history of CF

exists to determine whether they have one aberrant

CF gene and one normal CF gene. Compare cystic

fibrosis screening.

Cystic fibrosis screening: The performance of tests to

diagnose the presence or absence of the actual

disorder, in the absence of medical indications of

the disease or a family history of CF. This type of

diagnostic screening usually involves newborns,

but is rare except in Colorado and Wisconsin.

Compare cysticfibrosis carrier screening.

Cystic fibrosis transmembrane conductance regulator

(CFTR): The CF gene product, which regulates

chloride (Cl-) conductance and might be a Cl- ion

channel, the structure that governs Cl- entry and

exit in the cell. CFTR produced by a mutant CF

gene is frequently impaired, resulting in the

medical manifestations of CF in affected individuals.

DF508: A three base pair deletion in the CF gene that

results in a faulty CF gene product (i.e., a flawed

CFTR). This mutation results in the deletion of

one amino acid, phenylalanine, at position number

508 in CFTR. DF508 is the most common mutant

allele among the more than 170 mutations identified in the CF gene.

Deoxyribonucleic acid (DNA): The molecule that encodes genetic information. DNA is a doublestranded helix held together by weak bonds

between base pairs of nucleotides.

Discrimination: Differential treatment or favor with a

prejudiced outlook or action.

Dominant: An allele that exerts its phenotypic effect

when present either in homozygous or heterozy -

gous form.

Dot blot: A variation of Southern blotting that involves

placing DNA into discrete spots on a nylon

membrane. A probe or probes can be hybridized

to the membrane and diagnosis made rapidly.

DNA: See deoxyribonucleic acid.

DNA

DNA

DNA

analysis: A direct examination of the genetic

material, DNA, to reveal whether a individual has

a CF mutation. Also known as DNA test and DNA

assay.

band: The visual image, e.g., on a autoradiogram

or an ethidium bromide stained gel, that represents

a particular DNA fragment.

probe: Short segment of DNA labeled with a

radioactive or other chemical tag and then used to

detect the presence of a particular DNA sequence
280 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

through hybridization to its complementary sequence.

DNA sequence: Order of nucleotide bases in DNA.

Double helix: The ladder-like shape formed by two linear

strands of DNA bonded together.

Electrophoresis: Technique used to separate molecules

such as DNA fragments or proteins. Electric

current is passed through a gel and the fragments

of DNA are separated by size. Smaller fragments

migrate farther than larger pieces.

Enzyme: A protein that acts as a catalyst, speeding the

rate at which a biochemical reaction proceeds,

without being permanently altered or consumed

by the reaction so that it can act repeatedly.

Epidemiology: The scientific study of the distribution

and occurrence of human diseases, health conditions, and their determinants.

Eugenics: Attempts to improve hereditary qualities

through selective breeding.

Exocrine glands: Glands that secrete into ducts or onto

specific organ surfaces. Exoerine glands are

classified as serous (producing a watery substance) or mucous (producing a viscous substance). CF affects both types, increasing the salt

content of serous secretions and diminishing the

salt content of mucus secretions. Mucous exoerine

glands from individuals with CF then produce

thicker than normal secretions leading to obstruction of the glands’ ducts. Examples of exocrine

glands include lacrimal (tear) glands, sweat

glands, and part of the pancreas.

Exons: The protein-coding DNA sequences of a gene.

Compare introns.

Frequency: The number of occurrences of a given allele

within a given population.

Gel: The semi-solid matrix (e.g., agarosegeloracrylamide)

used in electrophoresis to separate molecules.

Gene: The fundamental physical and functional unit of

heredity. A gene is an ordered sequence of

nucleotide base pairs to which a specific product

or function can be assigned.

Gene mapping: Determining the relative locations of

different genes on chromosomes.

Gene therapy: The deliberate administration of genetic

material into the cells of a patient with the intent

of correcting a specific genetic defect.

Genetic code: The sequence of nucleotides, coded in

triplets along the mRNA, that determines the

sequence of amino acids in protein synthesis. The

DNA sequence of a gene can be used to predict the

mRNA sequence, and this genetic code can in turn

be used to predict the amino acid sequence.

Genetic counseling: A clinical service involving educational, informational, and psychosocial elements

to provide an individual (and sometimes his or her

family) with information about heritable conditions. Genetic counseling is performed by genetics

specialists, including physicians, Ph.D. clinical

geneticists, genetic counselors, nurses, and social

workers.

Genetic screening: The analysis of samples from asymptomatic individuals with no family history of a

disorder, groups of such individuals, or populations.

Genetic testing: The use of specific assays to determine

the genetic status of individuals already suspected

to be at high risk (e.g., family history or symptoms) for a particular inherited condition.

Genetics: The study of the patterns of inheritance of

specific traits.

Genome: All the genetic material in the chromosomes of

a particular organism; its size is generally given as

its total number of base pairs. The human genome

is 3.3 billion base pairs.

Genotype: The genetic constitution of an organism, as

distinguished from its physical appearance, or

phenotype.

Health maintenance organization (HMO): A health

care organization that serves as both payer and

provider of comprehensive medical services, provided by a defined group of physicians to an

enrolled, fee-paying population.

Hemoglobin (Hb): A protein that carries oxygen in red

blood cells. Sickle cell and thalassemia mutations

affect hemoglobin.

Heterozygote: A heterozygous individual, such as a CF

carrier.

Heterozygous: Having two different alleles at a particular

locus.

Homozygote: A homozygous individual.

Homozygous: Having the same alleles at a particular

locus.

Hybridization: The process of joining two complementary

strands of DNA, or of DNA and RNA, together to

form a double-stranded molecule.

Immunoreactive trypsin (IRT) test: An assay that

measures levels of pancreatic trypsin, a digestive

enzyme. As a protocol for newborn CF screening,

a drop of blood is isolated on a card, dried, and

chemically analyzed to detect elevated levels of

the enzyme. It is not intended to be a diagnostic

test.
Appendix F---Aronyms and Glossary . 281

In vitro: Literally, ‘‘in glass,’ pertaining to a biological

process or reaction taking place in an artificial

environment, usually a laboratory.

In vivo: Literally, “in the living,” pertaining to a

biological process or reaction taking place in a

living cell or organism.

Introns: DNA sequences interrupting the protein-coding

DNA sequences of a gene that are transcribed into

mRNA, but are spliced out of the rnRNA before

the rnRNA is translated into protein. Compare

exons.

Karyotype: A photomicrograph of an individual’s chromosomes arranged in a standard format showing

the number, size, and shape of each chromosome.

Ligase chain reaction (LCR): An in vitro process that

amplifies only the region of DNA directly underneath the known sequence to make millions of

copies of this sequence. Mutations differing by a

single base can be easily detected with this

technique.

Linkage: The proximity of two or more markers (e.g.,

genes, RFLP markers) on a chromosome. The

closer together the markers are the lower the

probability that they will be separated during

meiosis, and hence the greater the probability that

they will be inherited together.

Linkage analysis: The process of studying DNA markers

to trace the transmission of a particular gene and

a specific mutation in a particular family. This can

be performed only in families with a living CF

affected member or from DNA samples stored

from a deceased affected family member.

Locus: A specific, physical position on a chromosome.

Marker: A stretch of DNA with a known location on a

chromosome that is used as a point of reference

when mapping another locus. Markers can be

important to linkage analysis and diagnosing

genetic disease,

Meiosis: The process of reduction of genetic material and

cell division in the diploid progenitors of sex cells.

Meiosis results in four, rather than two, daughter

cells, each with a single set of chromosomes.

Messenger RNA (mRNA): A class of RNA produced by

transcribing the DNA sequence of a gene. An

mRNA molecule is involved in translating instructions from the DNA sequence into proteins.

Mutation: Changes in the composition of DNA.

Nucleotide: The unit of DNA consisting of one of four

bases—adenine, guanine, cytosine, or thymineattached to a phosphate-sugar group. The sugar

group is deoxyribose in DNA. In RNA, the sugar

group is ribose and the base uracil substitutes for

thymine.

Open enrollment: A health insurance enrollment period

during which coverage is offered regardless of

health status and without medical screening. Open

enrollment periods are characteristic of some

BC/BS plans and HMOs.

Phenotype: The appearance of an individual or the

observable properties of an organism that result

from the interaction of genes and the environment.

Compare genotype.

Polymerase chain reaction (PCR): An in vitro process

through which repeated cycling of the reaction

reproduces a specific region of DNA between two

sites, yielding millions of copies from the original.

Polymorphism: The existence of more than one form of

a genetic trait.

Preexisting condition: A condition existing before an

insurance policy goes into effect and commonly

defined as one which would cause an ordinarily

prudent person to seek diagnosis, care, or treatment.

Proband: The individual in a family first identified as

manifesting a given heritable trait.

Probe: A short segment of DNA tagged with a reporter

molecule, such as radioactive phosphorus (32P),

used to detect the presence of that particular

complementary DNA sequence.

Protein: A biological molecule whose structure is

Rated

determined by the sequence of nucleotides in

DNA. Proteins are required for the structure,

function, and regulation of cells, tissues, and

organs in the body.

premium: A premium with an added surcharge

that is required by insurers to cover the additional

risk associated with certain medical conditions.

Rated premiums usually range from 25 to 100

percent more than the standard premium.

Recombinant DNA technology: Processes used to form

a DNA molecule through the union of different

DNA molecules, but often commonly used to refer

to any techniques that directly examine DNA.

Recessive: An allele that exerts its phenotypic effect only

when present in homozygous form, otherwise

being masked by the dominant allele,

Reliability: The ability of a test to accurately detect that

which it was designed to detect and to do so in a

consistent fashion.
282 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Replication: The synthesis of new DNA from existing

DNA. PCR is an in vitro technology based on

principles of replication.

Restriction endonuclease: An enzyme that has the

ability to recognize a specific DNA sequence and

cut it at that sequence.

Restriction enzyme: See restriction endonuclease.

Restriction fragment length polymorphism (RFLP):

Variations in the size of DNA fragments produced

by a restriction endonuclease at a polymorphic

locus.

Restriction fragment length polymorphism (RFLP)

analysis: DNA technique using single-locus or

multilocus probes to detect variation in the DNA

sequence by revealing size differences in DNA

fragments produced by the action of a restriction

enzyme. See restriction fragment length polymorphism.

Reverse dot blot: Blotting in which allele-specific

oligonucleotides (ASOs) are immobilized on the

membrane. Key segments of the individual’s

unknown DNA are then amplified, labeled, and

hybridized to the probes on the membrane.

Ribonucleic acid (RNA): A chemical found in the

nucleus and cytoplasm of cells that plays an

important role in protein synthesis and other

chemical activities of the cell. The structure of

RNA is similar to that of DNA. There are several

classes of RNA molecules, including messenger

RNA, transfer RNA, ribosomal RNA, and other

small RNAs, each serving a different purpose.

RNA: See ribonucleic acid.

Sensitivity y: The ability of a test to identify correctly those

who have a disease.

Sex chromosomes: The X and Y chromosomes in human

Sickle

Sickle

beings that determine the sex of an individual.

Females have two X chromosomes in somatic

cells; males have an X and a Y chromosome.

cell anemia: An autosomal recessive disorder

affecting red blood cell flow through the circulatory system, causing complications in numerous

other organ systems. Sickle cell anemia predominantly occurs in individuals of African descent.

cell trait: The heterozygous state of sickle cell

anemia; sickle cell carrier status.

Single-gene disorder: Hereditary disorder caused by a

single gene (e.g., cystic fibrosis, Tay-Sachs disease, sickle cell anemia).

Somatic cells: Any cells in the body except reproductive

cells and their precursors.

Southern blot: The nylon membrane to which DNA has

adhered after the process of Southern blotting.

Southern blotting: The technique for transferring DNA

fragments separated by electrophoresis from the

gel to a nylon membrane, to which DNA probes

that detect specific fragments can then be applied.

Specificity: The ability of a test to identify correctly those

who do not have the characteristic which is being

tested.

Stigmatization: Branding, marking, or discrediting because of a particular characteristic,

Sweat test: An assay used to confirm CF that measures

levels of sodium (Na+

) and chloride (Cl-) ions.

These ions appear in high concentrations in

patients with CF. Sweating is induced by running

a low electric current through a pilocarpinesoaked gauze pad on the individual’s arm or back.

The amounts of Na+ and Cl- in the sweat can then

be determined to confirm or question a diagnosis

of CF.

Tag polymerase: DNA polymerase-the enzyme used to

form double-stranded DNA from nucleotides and

a single-stranded DNA template—isolated from

the bacterium Thermus aquaticus, which normally lives in hot springs, Taq polymerase can

withstand the high temperatures required in the

repeating cycles of polymerase chain reaction

(PCR).

Tay-Sachs disease: A lethal autosomal recessive disorder affecting the central nervous system which

results in mental retardation and early death.

Tay-Sachs disease predominantly occurs among

Jews of Eastern and Central European descent and

populations in the United States and Canada

descended from French Canadian ancestors.

Transcription: The synthesis of mRNA from a sequence

of DNA (a gene); the first step in gene expression.

Compare translation.

Translation: The process in which the genetic code

carried by mRNA directs the synthesis of proteins

from amino acids. Compare transcription.

Underwrite: The process by which an insurer determines

whether and on what basis it will accept an

application for insurance.

Wrongful birth: A malpractice claim in which the parents assert that failure to receive timely, accurate information robbed them of the opportunity

to avoid conception or birth of an affected child.

Wrongful life: A malpractice claim in which an affected

child asserts he or she was harmed by a failure to

give the parents an opportunity to avoid conception or birth. The claimant argues that to never

have existed would be better than to exist with

severe disabilities.
Index
Index

œ-thalassemia

carrier frequency among African Americans, 260

carrier screening for, 15, 231, 260

genetics of, 260

incidence among Asian newborns of, 260

stillbirths in Southeast Asia due to, 260

Abortion

cost of, 218

cost-effectiveness and assumptions about, 39-40, 213, 219,

224

effect on cost-efectiveness of, 40, 223-224

genetic counseling and, 45, 127

prenatal diagnosis of genetic disorders and attitudes toward,

28-29, 127, 190,219, 265

role in controversy over CF carrier screening, 15, 16, 60

Supreme court rulings on, 45, 127

Accreditation, 112-113

Adenosine dearninase deficiency, gene therapy for, 94

Adrenoleukodystrophy, health insurance difficulties and, 34,

200

Adult polycystic kidney disease (APKD)

health insurance difficulties and, 34,200

inheritance pattern of, 87

risk comprehension in families affected by, 143

Adverse selection

genetic tests and potential for, 178

health insurance and, 174

African Americans

ß-thalassemia mutations in, 259

CF carrier frequency among, 14, 145

frequency of ct-tha.lassemia carriers among, 260

frequency of CF live births among, 5,49,90,219

frequency of sickle cell anemia and trait in, 258

frequency of sickle cell anemia live births among, 258

frequency of sickle cell carriers, 258

government interest in addressing sickle cell anemia among,

15,51-52

see also Asian Americans; Caucasian Americans of European

descent; Hispanic Americans

Agency for Health Care Policy and Research-DHHS, 43

Alabama

disability statute of, 204

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Alaska

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Albania, frequency of AF508 in, 248

Alcohol, Drug Abuse, and Mental Health Administration

(ADAMHA), CF-related research funded by, 101, 102

Alcoholics, compulsory sterilization and, 51

Allele specific oligonucleotide (ASO) probes, 11,95,96,98

Alpha-1 -antitrypsin deficiency

gene therapy and, 6, 76

health insurance difficulties and, 34, 200

Alpha-fetoprotein. See Maternal serum alpha-fetoprotein

American Academy of Pediatrics (AAP), 119, 144

American Association of BioAnalysts, CLIA accreditation and,

113

American Board of Medical Genetics (ABMG)

certiilcation by, 24, 121

genetic counselors’ certitlcation and 4,23,50, 121, 152

American Caucasians of European descent. See Caucasian

Americans of European descent

American College of Medical Genetics, 123

American College of Obstetricians and Gynecologists (ACOG)

policy statement on CF carrier screening of, 123

policy statement on MSAFP screening of, 144

regulation of MSAFP test kits and, 119

American Medical Association (AMA)

codes of ethics and, 123

policy statement on CF carrier screening of, 123

American Osteopathic Association, CLLA accreditation and,

113

American Society of Human Genetics (ASHG)

MSAFP screening and, 144

policy statement on reproductive options, 127

policy statements on CF carrier screening of, 21, 123, 146

role in 1975 NRC report, 54

role in proficiency testing of, 36, 115

Americans With Disabilities Act of 1990 (ADA)

as a focus of congressional options to address genetic

discrumination, 42

definition of disability under, 33-34, 204

health insurance and, 35,42,206-207

relevance to genetics of, 34-35, 51, 202, 205-206

Arniloride, 6,76

Amniocentesis

prenatal diagnosis using, 147

reimbursement under Medicaid for, 28, 182-184

Arnpliflcation refractory mutation system (ARMS) multiplex

kit, 116,233,234

Arabs, sickle cell mutation in, 258

Arizona

genetic services funding in, 159

hereditary conditions and state law in, 202

Medicaid program in, 182

Arkansas

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

Artit3cial insemination, 15, 60, 61

Ashkenazic Jews

fkequency of carriers for Tay-Sachs disease among, 121, 254

frequency of AF508 in Israeli, 250

frequency of W1282X in, 91

incidence of Tay-Sachs disease among, 254

sensitivity of AF508+6 in, 10, 58, 146

Asian Americans

~-thalassemia mutations in, 259

CF carrier frequency among, 14, 145

frequency of CF live births among, 5,49,90,218

see also African Americans; Caucasian Americans of European descent; Hispanic Americans

Asian Indians, sickle cell mutations in, 258

Association of Schools of Public Health, 155

Australia

CF screening of newborns in, 73

–285–
286 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

membership in European Concerted Action on Cystic Fibrosis

of, 241

Austria

carrier scxeening pilot study in, 17, 238, 239

membership in European Concerted Action on Cystic Fibrosis

of, 241

Automation

affect on costs of, 37,44

as a factor affecting utilization of CF carrier tests, 20, 37-38

congressional options to address, 40, 43

Human Genome Project funding of, 37,99

impact on CF ca.mier screening of, 100

of DNA diagnostic procedures, 98-100

&thalassemia

carrier screening for, 15, 261-263

congressional interest in, 52, 259, 261

ethnic populations affected by, 259, 260

genetics of, 88,260-261

manifestations of, 259-260

State law against discrimination for, 202

Base case, assumptions used in cost-effectiveness, 39,220-221

Baylor College of Medicine

case of health insurance diftlculties and CF pnmatal screening, 33, 200

cost of CF mutation analysis at, 39, 216

privately funded pilot study at, 19, 161

Belgium

frequency of AF508 in, 248

frequency of AF508 in Antwerp, 248

membership in European Concerted Action on Cystic Fibrosis

of, 241

Biomedical Ethics Advisory Committee, U.S. congressional,

205

Blastomere analysis before implantation (BABI), prenatal

analysis using, 147-148

Blindness, compulsory sterilization and, 51

Blue Cross/Blue Shield (BC/BS) plans

1991 OTA survey of, 27-28,31-33,62, 194-195

attitude toward carrier status as preexisting conditions of, 31,

195

attitude toward fairness in using genetic tests of, 177

attitude toward genetic conditions as preexisting conditions

of, 31, 195

attitude toward medical information versus genetic information of, 31, 195

attitude toward option of using genetic information of,

177-178

demographics of respondents, 176-177

factors affecting insurability by, 31-32, 195-196

future use of genetic tests by, 32, 197-199

impact of genetic tests on, 32-33, 178

open enrollment under, 171, 172

regulation of, 25, 171

reimbursement for CF carrier tests by, 27, 181

reimbursement of genetic counseling by, 28, 182

structure of, 170-171

see also Commercial health insurers; Health insurance;

Health insurers; Health maintenance organizations

Boston University, cost of CF mutation analysis at, 39, 216

Bulgaria

frequency of AF508 in, 248

membership in European Concerted Action on Cystic Fibrosis

of, 241

Bureau of Health Care Delivery and Assistanc*DHHS,

support for genetics education of nurses by, 155

Bureau of Maternal and Child Health and Resources Development—DHHS, genetics professional education and training SUPPOIt by, 154

California

a-thalassernia carrier screening in, 260

court ruling on Tay-Sachs carrier screening and standard of

care, 121-122

genetic services funding in, 159

hereditary conditions and state law in, 202,203

Hereditary Disorders Act of 1990,203

licensing and regulations for DNA laboratories in, 36, 114

Medicaid reimbursement for genetic services in, 183

MSAFP screening in, 151

non-master’ s-level counselors and sickle cell programs in,

155

prenatal screening fees as a source of genetic services finding

in, 26, 53

reproductive stigmatization and Bree Walker Lampley in, 29,

191

Tay-Sachs carrier screening of Orthodox Jews in, 256

wrongti life claims in, 130

Canada

~-thalassemia carrier screening in, 261

CF carrier screening pilot study in, 19,29,150, 162,191-192

ELSI grant to survey views of genetic specialists in, 55

frequency of AF508 in, 91,247,253

median CF smiva.1 data from, 6, 77

Tay-Sachs carrier screening in, 254,255, 256,257

Tay-Sachs carrier screening of Orthodox Jews in Montreal,

256

Caregiving, costs of, 38,215-216

Carrier. See Carrier screening; Carrier status; Cystic fibrosis

carrier screening

Carrier screening

definition used in OTA report of, 4,50

for jh.halassemia, 259-263

for sickle cell trait, 258-259

for Tay-Sachs, 255-257

goals of, 57

value of, 45, 54, 213-214, 226

see also Cystic fibrosis carrier screening

Carrier status

ADA and, 35,205, 206

frequency among Caucasians of positive CF, 3, 10,58,90

health insurers’ attitudes toward, 31, 195,200

number of Americans with positive CF, 8, 49, 90

stigmatization of, 28-29, 189-192

Camier testing

definition used in OTA report of, 4,50

see also Cystic fibrosis carrier testing

Caucasian Americans of European descent

carrier frequency of CF among, 14, 58,90, 121, 145

carrier fxequency of Tay-Sachs disease among, 121

frequency of CF live births among, 5,49,90, 121

see also African Americans; Asian Americans; Hispanic

Americans

Cellmark Diagnostics, U.K.
Index . 287

development of CF mutation analysis kit, 116

U.K. pilot programs and use of CF mutation analysis test kit

of, 233, 234

Centers for Disease Control, 119

Certification

of genetic specialists, 23, 120-121

see also Licensing

Cetus Corp., 217

Chest physical therapy (PT)

cost of, 216

elements of, 76

time devoted to, 38, 216

Chevra Dor Yeshorim, 256

Children’s Hospital Oakland Research Institute, NIH-funded

pilot study at, 18, 157

China

ct-thalassemia carrier screening in, 260

~-thalassernia carrier screening in, 262-263

~-thalassernia mutations in, 259

Chloride ion (Cl-), concentration as an indicator of CF, 9, 72

Chorionic VillUS saqiing (CVS)

cost of, 218

prenatal diagnosis of CF using, 147

reimbursement under Medicaid for, 28, 182-184

Chromosome

number 7-6, 8, 58, 90

structure and organization in humans, 6, 7, 58, 85, 87

translocations and health insurance difficulties, 200

Chromosome analysis, reimbursement under Medicaid for, 28,

182-184

Civil Rights Act, relevance to genetics of Title VII of the, 51,202

Civilian Health and Medical Program of the Uniformed Services

(CHAMPUS), health care coverage under, 25, 170

Clinical laboratories

congressional options for regulation of, 40, 42

regulation of 35-37, 111-116

see also Clinical Laboratory Improvement Amendments of

1988

Clinical Laboratory Improvement Amendments of 1988 (CLIA)

accreditation under, 36, 112-113

congressional options for, 42

DNA tests and impact of, 36, 114, 132

facilities covered by, 36, 112, 113

monitoring laboratory performance under, 113

professional societies and, 36, 114-116

proficiency testing requirements of, 37, 113, 114

regulatory requirements as a function of complexity under,

112

sanctions under, 112, 113-114

State authorities under, 36, 113, 114

Collaborative Research, Inc., cost of CF mutation analysis by,

39, 216

College of American Pathologists (CAP)

CLIA accreditation and, 36, 113

DNA-based test proficiency pilot studies of, 36, 115

Colorado

CF screening of newborns in, 4,50,73

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

newborn screening fees as a source of genetic services funding

in, 26, 53

Commercial health insurers

1991 OTA survey of, 27-28,31-33,62, 194-195

attitude toward carrier status as preexisting conditions of,31,

195

attitude toward fairness in using genetic tests of, 32-33, 177

attitude toward genetic conditions as preexisting conditions

of, 31, 195

attitude toward medical information versus genetic information of, 31, 195

attitude toward option of using genetic information of,

177-178

demographics of respondents, 176-177

factors affecting insurability by, 31-32, 195-196

fiture use of genetic tests by, 32, 197-199

impact of genetic tests on, 32-33, 178

regulation of, 25, 175

reimbursement for CF carrier tests by, 27, 180-181

nAr-nbursement of genetic counseling by, 27, 182

see also Blue Cross/Blue Shield plans; Health insurance;

Health insurers; Health maintenance organizations

Confidentiality

as duty in genetic counseling, 22-23, 128-129

b~ach of, 22-23, 131, 148

codes of ethics and, 128

conditions identified by 1983 President’s Commission report

that override, 128-129

ELSI grants funded that relate to, 55-56

inductive screening and, 148

States’ roles in protecting, 22, 128

Congress, U.S.

clinical laboratory regulation and, 35-37, 111-113

Human Genome Project and, 3,5, 54

interest in genetics and public health of, 51-52

issues and options for, 4045

President’s Cornrnis sion for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research and,

52,54

see also General Accounting OffIce; House Committee on

Energy and Commerce; House Coremittee on Science,

Space, and Technology; Office of Technology Assessment

Comecticut

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Consumers

concerns about health insurance of, 29-30, 192, 194, 200-201

interest in CF carrier screening of, 20-21, 121

perceptions of genetic risk by, 24, 142-143

Cooley’s anemia. See ~-thalassemia

Cordocentesis, prenatal analysis using, 147

Cornell University Medical College

cost of CF mutation analysis at, 39, 216

privately funded pilot study at, 19, 161

Cost-effectiveness

as a factor affecting utilization of CF carrier tests, 20, 3840

caveats about, 38, 213-214, 224-226

effect of assumptions on, 40, 222-224

variables and assumptions used in analysis of, 3940,218-220

Cost offsets, calculation of, 222

costs

as a factor affecting utilization of CF carrier tests, 20, 3840

calculation of base case and alternative scenario, 220-222

CF-related nonmedical (caregiving), 38,215-216
288 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

components of CF-related medical, 38, 214-215

not included in OTA analysis, 214

of CF carrier screening in the general population, 216-218

of CF mutation analysis, 39,60,216

of CF treatment in the United Kingdom, 231

range of CF-related medical, 38, 215

with no carrier screening, 220

Council of Regional Networks for Genetic Services (CORN)

DNA-based test proficiency @ot studies of, 36, 115

Federal funding for, 25,26,36,53, 154

Courts, role in ensuring quality of genetic services of, 21, 23,

111, 124, 129

Coverage. See Reimbursement; Health insurance

Cuba, membership in European Concerted Action on Cystic

Fibrosis of, 241

Customary physician practice. See Standards of care

Cyprus, @_mlassernia carrier screening program in, 262

Cystic fibrosis (CF)

ADA and, 34-35,205

age distribution of individuals with, 7, 77-78

births a.MUtiY, 3,49

births to couples with no family history, 3, 50,61

chest physical therapy for, 76

costs of, 38, 214-215

diagnosis of, 4, 72-73

gene therapy for, 5,6,76,94

genetics of, 8-9,90-94

health insurance difficulties and, 33,34,79,200

history of, 49

in the United Kingdom, 231-232

incidence among American newborns of, 5,49,69, 90

inheritance pattern of, 3,6,8,50,88,90

life insurance and, 176

median survival, 5, 6, 77

medical management of, 73-76

number of people in the United States with, 3,49

number of potential carriers in the United States for, 8,49,90

organ systems affected by, 3, 4-5, 70

pathology of, 4,69-72

pha.n-naceuticals used to heat, 74-75,76

prenatal diagnosis of, 147-148

prognosis, 4,5-6,7,77-78

psychological aspects, 6,78-79

research funding for, 3-4, 100-103

risk to carrier couples of having a child with, 10,59

tests to detect, 72-73

treatment for, 5, 6,73-77

wrongful birth claim for, 130

Cystic fibrosis carrier screening

ability to self-pay and access to, 27, 121

anxiety and, 148, 151

congressional issues and options for, 40-45

controversy surrounding, 11, 14-15, 56-61

cost-effectiveness of, 39-40, 218-226

costs of, 39, 216-218

couples approach to, 17, 236

definition used in OTA report of, 4, 10,50

discrumination issues of, 14, 60, 189-207

distinction between CF carrier testing and, 4,50

education issues for, 24, 149-150

future implications of, 43-45

genetic counseling scenario for, 145-150

goals of, 57

in the United Kingdom, 17, 231-242

in the United Kingdom compamd to the United States, 17,

231,232,241-242

insurability and, 31-32, 195-196

lessons from other genetic screening programs for, 15-16,24,

143, 144, 151-152,263-265

medical malpractice and, 20-21, 23, 122, 123, 129-131

number of individuals potentially involved in, 16, 58

opposition to, 14-15, 59, 60-61, 121, 122-124

pilot studies, 15-16, 18-19,52, 101, 157-158, 160-163

population targets, 16,58, 150-152, 157-158, 160-163,239

preexisting conditions and, 31, 195

pressures for and against, 11, 14-15,56-61

psychological aspects of, 141

quality assurance of, 35-37,60-61, 111-132

reimbursement for, 27-28, 179-182

sensitivity of detection of, 10-11, 13-14, 58-59, 146-147

setting for, 25, 145

standards of Care and, 20-21, 121-124

support for, 15, 59-60, 61, 124

technologies used in, 12,95-100

trends, 17-18, 20,61

utilization of, 18, 20, 61

value of, 45, 54, 213-214, 226

see also Cystic fibrosis carrier tests

Cystic fibrosis carrier testing

definition used in OTA report of, 4,50

distinction between CF can-ier screening and, 4,50

Cystic fibrosis carrier tests

accuracy of, 10, 58

automation of, 37-38, 98-100

based on function of CIWR, 9,93

cost of, 39, 60, 216, 225

development and regulation of kits for, 37, 116-120

DNA technologies used in, 12,95-100

limits of, 10,98

number of, 9-10, 18, 20, 61

number of facilities performing, 61, 216

reimbursement for, 27, 179-182

risk of child with CF after using, 11, 13, 59, 146-147

sensitivity of, 10-11, 13-14,58-59, 146

use of mouthwash samples for, 17, 231

see also Cystic fibrosis carrier screening; Cystic fibrosis

mutation analysis

Cystic fibrosis centers

estimate of CF-related caregiving time by, 215-216

specialized treatment at, 73,74

Cystic Fibrosis Foundation (CFF)--United States

acceptance of DNA arudysis as positive diagnosis by, 73

carrier screening and, 16, 52, 60

clinical centers of, 73, 74

collaboration with NIH to fund research of, 102, 103

cost estimates based on data horn, 214-215

data collection through annual suxvey by, 73, 129

estimate of median lifespan by, 5

patient mgistxy of, 73

research fimded by, 100, 101, 103

Cystic fibrosis gene

localization of, 3,6,58,90

mutations in, 9, 58, 91

product of, 8,91,93
Index Q 289

StrUCtUrt3 of, 8-9, 91, 92

Cystic Fibrosis Genetic Analysis Consorti urn-North Americ~

241, 247

Cystic fibrosis mutation analysis

development and regulation of kits for, 37, 116-120

diagnostic use of, 73,99

DNA techniques used in, 12,95-100

pretest education about, 141-142

reimbursement for, 27, 179-182

risk of child with CF after, 146-147

sensitivity of, 10-11, 13-14, 58-59, 146

testing relatives and, 145-146, 148

see also Cystic fibrosis carrier screening; Cystic fibrosis

carrier tests

Cystic fibrosis mutations

automated detection of, 37-38, 99, 100

correlation with prognosis, 9, 91

DNA technologies to detect, 12,95-100

frequency among African Americans, 14, 145

frequency among American Caucasians of, 14, 58, 90, 145,

253

frequency among Asian Americans, 14, 145

frequency among Hispanic Americans, 14, 145

frequency in Europe of, 10,247-253

international variation, 9, 10, 246-253

number of, 9, 58, 91

see also specific mutations

Cystic Fibrosis Research Trust (CF Trust)-United Kingdom

CF carrier screening pilot programs funded by, 17, 231,

233-238

role in CF carrier screening of, 16, 233

Cystic fibrosis screening

deftition used in OTA report of, 4,50

see also Newborn screening

Cystic fibrosis testing

deftition used in OTA repofi of, 4,50

see also Newborn screening

Cystic fibrosis transmembrane conductance regulator (CFTR)

effect of mutation on, 9, 91, 93

fimction of, 9,91, 93

structure of, 92

Czech and Slovak Federal Republic

frequency of AF508 in, 248

frequency of AF508 in Bohemi@foravia, 248

frequency of AF508 in Slovakia, 248

membership in European Concerted Action on Cystic Fibrosis

of, 241

Czechoslovakia (former). See Czech and Slovak Federal Republic

Darwin, Charles, 51

Deafness, compulsory sterilization and, 51

Defensive medicine. See Medical malpractice

Definitions, used in OTA report, 4,49-50

Delaware

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

Denmark

CF carrier screaing in, 17, 238,239

frequency of AF508 in, 248

homogeneity of AF508 in, 247

membership in European Concerted Action on Cystic Fibrosis

of, 241

Deoxyribonucleic acid (DNA)

function and organization of, 85

proteins and, 86

replication of, 85-86, 88,97

StrUCtllR of, 7, 85, 86

see also DNA tests

Department of Defense, U.S. (DOD), 170

Department of Energy, U.S. (DOE)

ELSI Program of, 5,55-56

Human Genome Project funding by, 101

Joint Subcommittee on the Human Genome (ND-I) of, 35,206

public education grant funded by ELSI Program of, 24,

149-150

Department of Health and Human Services, U.S. (DHHS), 112,

154

AF508

automated detection of, 99

detection of, 9-11,59,99

frequency in Caucasian Americans of, 9,58,91, 146

homogeneous occurrence in Denmark of, 247

occurrence in Europe of, 13-14, 247-252, 253

percent of carrier couples detected by, 146

percent of CF carriers detected with test for, 9, 10,58,247

severity of, 91

Diabetes, CF-associated, 71

Diagnosis

of @halassemia, 261

of CF, 4, 72-73

of sickle cell anemia, 258

of Tay-Sachs disease, 254-255

Digestive therapy, 75

Disability

definition under the ADA of, 33-34,204-205

Medicare coverage and, 169

State law and, 204

stigmatization of, 16, 29, 189-191

Discrirnination

ADA and genetic, 34-35,51,202,205-206

as a factor affecting utilization of CF carrier tests, 20, 28-35

concerns stemrning from CF carrier screening, 28-35,60

congressional options to address genetic, 40, 42

definition of, 189

sickle cell screening and, 259

U.S. law and genetic, 33-35,202-207

see also Stigmatization

District of Columbia

disability law in, 204

genetic semices funding in, 26, 159

Medicaid reimbursement for genetic services in, 183

DNA, See Deoxyribonucleic acid

DNA sequencing, 98-100

DNA tests

CLIA impact on, 36, 114, 132

diagnosis of CF using, 4,73

impact of intellectual property protection on utilization of, 44,

217

regulation of clinical laboratories performing, 35-37, 112-116

regulation of kits for, 37, 116-120

reimbursement under Medicaid for, 28, 182-184
290 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

techniques used in, 95-100

see also Cystic fibrosis mutation analysis; Tests

DNase, 6,76

Dot blot, 12,95, 96,98

Dot blot, reverse, 12,98,99

Down syndrome

health insurance difficulties and, 34, 200

MSAFP screening and, 16, 143, 144

Drugs. See Pharmaceuticals

Duchenne muscular dystrophy, inheritance pattern of, 88

East Germany (former), See Germany

Economic considerations

costs of CF, 38, 214-218

costs of CF carrier screening, 39, 216-218

genetic tests and health insurers’ evaluation of, 32-33,

178-179

human capital approach, 214

pressure to screen stemmin g from, 14, 60

see also Cost-effectiveness; Costs; Financing; Reimbursement

Ectrodactyly, 29, 191

Education

average medical school curriculum for genetics, 25, 151

congressional issues and options for professional training and,

40,4142

congressional issues and options for public, 4041

cost of pretest, 217-218

ELSI grants funded that relate to, 55-56

of genetic specialists, 25, 152, 153-154

of health care professionals, 25, 151, 155

of public, 15, 24, 149-150

pretest, 141-142,224-225

SPRANS funding for, 26,53, 160

Electrophoresis, 12, 95,96, 99

Employee Retirement Income Security Act of 1974 (ERISA)

exemption from State insurance regulation under, 27, 171

health care benefits under, 194

health care plans under, 27, 171

OTA workshop on genetic tests and, 276

relationship to ADA of, 35, 42, 194

see also Self-funded employe~

England

frequency of AF508 in, 231,252

membership in European Concerted Action on Cystic Fibrosis

of, 241

Tay-Sachs carrier screening in, 255

see also United Kingdom

Epidemiology

of AF508 in Euro~, 10, 247-252

of AF508 in North American subpopulations, 253

of mutations for CF, 91, 247-253

of mutations for CF in Europe versus North America, 253

F,qual Employment Opportunity Coremission, U.S. (EEOC),

genetics and regulations implementing the ADA of, 35,

205, 206

Ethical considerations

ELM grants funded that relate to, 55-56

of gene therapy, 94

of genetics and health insurance, 193

OTA report and, 62

Ethical, Legal, and Social Issues (ELSI) Program-DOE

as a focus of congressional options to enhance professional

education and training, 42

as a focus of congressional options to improve public education in genetics, 41

grants funded by, 56-56

public education grant funded by EL.SI, 149-150

total funding for, 5, 55

Ethical, Legal, and Social Issues (ELSI) Program-NIH

as a focus of congressional options to enhance professional

education and training, 42

as a focus of congressional options to improve public

education in genetics, 41

CF carrier screening pilot studies funded by, 16,101,157-158

development of approach for pilot studies, 156-157

grants funded by, 5,55-56

total funding for, 5, 55

Ethical, Legal, and Social Issues Working Group-NII-I/DOE,

35, 156,206

Eti-Twks, sickle cell mutation in, 258

Eugenics

history of, 51

public health goals of genetic screening and potential

perception of, 57

Europe

automation of DNA analysis in, 100

frequency of CF mutations in, 9-10,247-253

Tay-Sachs carrier screening of Orthodox Jews in, 256

see also specific countries

European Concerted Action on Cystic Fibrosis, 241, 247

European Working Group on Cystic Fibrosis, 247

Exocrine glands, effect of CF on, 69

Fabry disease, health insurance difficulties and, 34,200

Fair Housing Amendments Act of 1988,202,204

Family history

CF carrier risk after negative test when positive, 146

CF carrier risk when positive, 145

likelihood of reimbursement for CF mutation tests with

positive, 27-28, 180, 181

Federal Bureau of Investigation, 55

Federal Communications Commission (FCC), 29, 191

Federal Fair Credit Reporting Act, 175

Federal Food, Drug, and Cosmetic Act of 1938, 116

Federal Government

funding for genetic services by, 25,26,52-53, 158-160

genetics and, 16,51-56, 155-160,202,203-207

regulation of clinical laboratories by, 35-37, 111-116

regulation of medical devices by, 37, 116-120

see also individual agencies

Financing

as a factor affecting utilization of CF carrier tests, 20, 25, 27

private, 25,27, 170-174

public, 25, 169

Finland, frequency of AF508 in, 248

Florida

genetic services funding in, 159

hereditary conditions and state law in, 202

high-risk insurance pool in, 170

mandato~ reporting of birth defects in, 128

Medicaid reimbursement for genetic sexvices in, 183

Tay-Sachs carrier screening in, 256

Tay-Sachs carrier screening of Orthodox Jews in, 256
Food and Drug Mrmm“ “stration (FDA)

congressional oversight of, 4243

gene therapy and approval by, 94

MSAFP and, 119, 144

new CF therapies and approval by, 6, 76

regulation of in vitro diagnostics by, 37, 117

regulation of medical devices by, 37, 116-120

regulatory future of CF mutation test kits and, 37, 118-120

regulatory status of reagents used in CF carrier analysis and,

116

Fortune 500 companies, assessment of health insurance risk of

potential employees by, 30,42, 192

Fragile X syndrome

genetics of, 87, 265

health insurance difficulties and, 34, 200

prenatal diagnosis and screening for, 265

France

frequency of AF508 in, 248

frequency of AF508 in Brittany (Celtic), 249

frequency of AF508 in Lyon, 249

frequency of AF508 in Paris, 249

frequency of AF508 in Southern, 249

membership in European Concerted Action on Cystic Fibrosis

of, 241

French Canadians, Tay-Sachs disease and carrier screening in,

254, 255

Funding

CF carrier screening pilot study, 15-16, 52, 101, 157-158,

160-163

CF-related research, 3-4, 100-103

for ELSI Programs, 5,55-56

Federal and State genetic services, 25, 52,53

Human Genome Project, 5,54

lessons from past carrier screening programs, 15, 263

Future prospects, 43-45,61

Galton, Francis, 51

Gastrointestinal (GI) system, effect of CF on, 3, 70-71

Gene

CF, 3,6-9,91,92

definition of, 3, 85

Gene therapy

clinical trials under way, 94

percent CFF research budget toward, 103

potential for CF, 5,6,76,94

General Accounting Office (GAO), investigations of FDA

medical device regulation by, 120

General practitioner (GP)---United Kingdom

CF carrier screening and involvement of, 233-234,238,239,

242

role in genetic services of, 231

GeneScreen, cost of CF mutation analysis by, 39,216

Genetic analysis

definition used in OTA report of, 4,50

see also Genetic screening; Genetic testing; Genetic tests

Genetic assays

definition used in OTA report of, 4,50

see also Genetic screening; Genetic testing; Genetic tests

Genetic counseling

abortion and, 45, 127

avoiding stigmatization with nondirective, 29, 192

CF carrier screening context and, 145-150

communicating risk and, 22, 24, 142-143

compensation for inadequate, 23, 129-131

components of, 22, 126-127

confidentiality and, 22-23, 128-129, 131

cost of post-test, 217

deftition used in OTA report of, 4,50, 153

duties of care for, 22-23, 124-129

health care professionals who perform, 4,24, 50

increased volume of genetic tests and impact on, 24, 151,

152-155

lessons from past carrier screening programs, 143, 144, 152,

264

need for sufficient and appropriate, 22, 141-144, 149

post-test, 148-149

reimbursement by health insurers for, 28, 179, 180, 181-182

reimbursement under Medicaid for, 28, 182-184

standard for, 22-23, 126-127

see also Genetic services

Genetic counselors

1991 OTA survey of, 21,24,33,62, 121, 123, 141, 145, 148,

149, 150, 151, 153, 154, 180, 199-202

deftition used in OTA report of, 4,50, 152

education and training of, 25, 41, 153

Genetic diseases

ADA and, 34-35,205-206

approximate number of, 5, 54, 86

health insurers’ attitudes toward, 31, 195-197

see also Carrier status; Genetic information; specific disorders

Genetic information

access to health care and, 29-31, 33, 193-194

use by insurers in rating, 32, 196-197

use by insurers in undenw-iting, 31-32, 195-196

Genetic screening

1975 NRC report on, 54

1983 report of the President’s Commission for the Study of

Ethical Problems in Medicine and Biomedical and

Behavioral Research on, 45, 52, 54

definition used in OTA report, 4, 50

public health and, 57

reimbursement for, 27, 179

see also Genetic testing

Genetic screening program

OTA deffition as applied to CF carrier screening, 4, 50

see also ct-thalassemia; ~-thalassemia; Sickle cell anemia;

Tay-Sachs disease

Genetic services

as a factor affecting utilization of CF carrier tests, 20-23

decline in funding for, 25,52,53

ensuring quality of, 22-23, 120-131

Federal funding for, 25, 26, 52,53, 158-160

impact of CF carrier screening on, 24-25, 60-61, 151, 153

impact of Human Genome Project on, 14-15, 53

in the United Kingdom, 17, 231-233

other funding sources for, 25, 53

reimbursement for, 27-28, 179-184

State funding for, 25,26, 53

see afso Genetic counseling

Genetic testing

definition used in OTA report of, 4,49-50

see also Genetic screening

Genetic tests
292 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

access to health insurance after using, 33, 34, 199-202

definition used in OTA report of, 4,50

health insurers’ attitudes toward, 32, 197-199

public attitudes toward, 20-21,62-63, 143, 190

see also DNA tests; Genetic screening; Genetic services;

Genetic testing; specific conditions

Genetics

basic principles of, 3,6,7, 85-86

human disease and, 86-87

of c+thalassernia, 260

of ~-thalassernia, 260-261

of CF, 3, 6, 8, 90-94

of Fragile X syndrome, 87, 265

of sickle cell anemia, 258

of Tay-Sachs disease, 254-255

Genetics & IVF Institute

cxst of CF mutation analysis at, 39, 216

privately funded pilot study at, 19, 161-162

Georgia

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic semices in, 183

Germany

frequency of AF508 among Tbrkish population in, 251

frequency of AF508 in Berlin, 249

frequency of AF508 in former East, 249

frequency of AF508 in former West, 249

membership in European Concerted Action on Cystic Fibrosis

of, 241

Great Britain, See United Kingdom

Greece

~-thalassemia carrier screening program in, 262

frequency of AF508 in, 249

membership in European Concerted Action on Cystic Fibrosis

of, 241

Orthodox Church and ~-tha.lassemia screening in, 262

sickle cell mutation in, 258

Group Health Association of America, 176

Guthrie spots, 71

Guy Hospital-Lmdon, CF carrier screening pilot program at,

17,233,238,239

H & H Music Co., 194

Hahnemann University, cost of CF mutation analysis at, 39,216

Hawaii

a-thalassemia carrier screening in, 260

fl-thahmemia carrier screening in, 260

genetic serviees funding in, 159

genetics education, technical assistance, and training funding

in, 160

Hereditary Anemia Project of, 260

Medicaid reimbursement for genetic services in, 183

Health care coverage

impact of genetics on access to, 33,34,44, 193-194, 199-202

of U.S. population, 25-26, 169

private financing of, 25, 170-174

public financing of, 25, 169-170

see also Health insurance

Health Care Financing Administration (HCFA)

congressional oversight of, 42

regulatory authority under CLIA of, 36, 112-114

Health insurance

ADA and, 35,206-207

consumer concerns about access to, 29-30, 33, 192, 194,

200-201

ethical considerations of, 193

impact of genetics on access to, 34, 193-194, 199-202

individual, 25, 172, 174

medically underwritten groups and, 25, 172, 174

MIB and individual, 174-176

OTA workshops on genetics and, 276

regulation of, 25, 175

risk and employability, 30, 192

t’ypeS of, 25, 169-174

see also Financing

Health Insurance Association of America (I-IL&4), 176, 197

Health insurers

1991 OTA st.uvey of, 27-28, 31-33, 62, 176-179, 180-182,

193-199

attitude toward carrier status as preexisting conditions of, 31,

195

attitude toward fairness in using genetic tests of, 32-33, 177

attitude toward genetic conditions as preexisting conditions

of, 31, 195

attitude toward medical information versus genetic information of, 31, 195

attitude toward option of using genetic information of,

177-178

factors affecting insurability by, 31-32, 195-196

future use of genetic tests by, 32, 197-199

genetic risk factors and attitudes of, 193-197

impact of genetic tests on, 32-33, 178

regulation of, 25, 175

reimbursement of CF carrier tests by, 27, 180-182

reimbursement of genetic counseling by, 28, 182

see also Blue Cross/Blue Shield plans; Commercial health

insurers; Health insurance; Health maintenance organizations; Medicaid; Reimbursement; Self-funded employen

Health maintenance organizations (HMOS)

1991 OTA survey of, 27-28, 31-33,62, 194-195

attitude toward carrier status as preexisting conditions of, 31,

195

attitude toward fairness in using genetic tests of, 177

attitude toward genetic conditions as preexisting conditions

of, 31, 195

attitude toward medical information versus genetic information of, 31, 195

attitude toward option of using genetic information of,

177-178

demographics of respondents, 176-177

factons affeeting insurability by, 31-32, 195-196

future use of genetic tests by, 32, 197-199

impact of genetic tests on, 32-33, 178

regulation of, 25, 171-172

~imbursement for CF carrier tests by, 27, 181

reimbursement of genetic counseling by, 28, 182

structure of, 171

see also Blue Cross/Blue Shield plans; Commercial health

insurers; Health insurance; Health insurers

Health Resources and Semiees Ad.mims“ tration-DHHS, support for genetics education of nurses by, 155

Hemophilia, health insurance diffktdties and, 34,200

Hemophilia A
Index. 293

confidentiality and genetic counseling for, 129

health insurance difficulties and, 34, 200

inheritance pattern of, 88

Hemophilia B, inheritance pattern of, 88

Hispanic Americans

CF carrier frequency in, 14, 145

frequency of CF live births among, 5,49,90, 219

see also African Americans; Asian Americans; Caucasian

Americans of European descent

History

of CF, 3, 49

of eugenics, 51

of U.S. genetic screening programs, 15, 52

of U,S. legislation related to genetics, 15, 51-52

Hitler, Adolph, 51

Ho ffmann-La Roche, Inc.

patent rights for PCR and, 217

See also Roche Biomedical Laboratones; Roche Molecular

Systems

Holmes, Justice Oliver Wendell, 51

Hong Kong

ct-thahssemia camier screening in, 260

~-thalassemia carrier screening in, 262-263

House Committee on Energy and Commerce, U. S., iii, 3

House Committee on Science, Space, and Technology, U. S., iii,

3

Howard Hughes Medical Institute (HHMI), CF-related research

funded by, 100, 103

HUGA-1—Japan, 100

Human Genome Project

Congress and, 3,5,54

cost of, 5, 54

ELSI Programs of, 5,55-56

impact on genetic services of, 14-15, 53

impact on health care access of, 44, 192

impact of intellectual property protection on 44, 217

National laboratories and, 98, 100, 193-194

SCOW of, 54-56

stigmatization and, 29, 189

Hungary, frequency of AF508 in, 249

Huntington disease

health insurance difficulties and, 34, 200

inheritance pattern of, 87

ICI 200,800,6,76

Idaho

cofildentiality of medicaJ information in, 131

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

Illinois

conildent.iality of medical information in, 131

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditary conditions and state law in, 202

Medicaid reimbursement for genetic services in, 183

Tay-Sachs carrier screening of Orthodox Jews in, 256

Irnmunoreactive trypsin (IRT) test

mechanics of, 72-73

newborn screening using, 73

Indian Health Service, 169

Indiana

genetic services funding in, 159

mandato~ reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

wrongful life claims in, 130

Individuals With Disabilities Education Act of 1990, 202

Inductive screening

as relates to CF carrier status, 148

effect on cost-effectiveness of, 225

Infertility

as a factor in cost-effectiveness, 219, 221

related to CF, 71

Informed consent, role of genetic counseling in, 126-127

Inheritance, modes of, 87-89

Institute of Medical Genetics—Wales, 233

Instrumentation. See Automation

Insurance. See Health insurance; Life insurance

Integrated Genetics

cost of CF mutation analysis by, 39, 216

privately funded pilot study and, 19, 162-163

Intellectual property

impact on costs of DNA-based analyses, 39, 216, 217

issues arising from Human Genome Project, 39, 44, 217

PCR and, 39, 217

Interested parties, CF carrier screening and, 56, 58-61

International Society of Nurses in Genetics, 62, 155,200

Iowa

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditary conditions and state law in, 202

mandatoxy reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

Iran, sickle cell mutation in, 258

Ireland, Republic of

frequency of AF508 in, 249

membership in European Concerted Action on Cystic Fibrosis

of, 241

Israel

frequency of AF508 among Arabs in, 250

frequency of AF508 among Ashkenazic Jews in, 250

frequency of AF508 among Non-Ashkenazic Jews in, 250

frequency of AF508 among Sephardic Jews in, 250

frequency of AF508 in, 250

membership in European Concerted Action on Cystic Fibrosis

of, 241

Tay-Sachs carrier screening of Orthodox Jews in, 256

Tay-Sachs disease and carrier screening in, 255

Italy

carrier screening pilot study in, 17, 238, 239

frequency of AF508 in, 250

frequency of AF508 in Campania, 250

frequency of AF508 in Centml/Southem, 250

frequency of AF508 in Northern, 250

frequency of AF508 in Rome/Verona, 250

frequency of AF508 in Sardinia, 250

membership in European Concerted Action on Cystic Fibrosis

of, 241

sickle cell mutation in, 258
294 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Japan

automation of DNA analysis in, 100

Tay-Sachs carrier screening in, 255

Johns Hopkins University

cost of CF mutation analysis at, 39, 216

NIH-funded pilot study at, 18, 158

Joint Commission on Accreditation of Healthcare Organizations, CLIA accreditation and, 36, 113

Joint Subcommittee on the Human Genome—NIH/DOE, 35,

206

Joint Working Group on Ethical, Legal, and Social Issues

(ELSI)--NIH/DOE, 35, 156,206

Judiciary. See Courts; Supreme Court, U.S.

Kaiser Permanence Health Care System, privately tided pilot

study by, 19, 162-163

Kansas

genetic services funding in, 159

genetics and public education in, 24, 149

Medicaid reimbursement for genetic services in, 183

Kentucky

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Laboratories. See Clinical laboratories

Lacrimal glands, effect of CF on, 69

Lawrence Berkeley Laboratory, 100

Legal considerations, ELSI grants funded that relate to, 55-56

Legislation, U.S.

related to genetic disease, 15, 51-52

see also specific laws

Liability. See Medical malpractice

Licensing

fees for royalty, 39,216,217

of genetic specialists, 23, 120-121

see also Certification

Life insurance

CF and, 176

confidentiality of genetic test information and, 129

MIB and, 174-175

Ligase chain reaction (LCR), 97

Linkage analysis, 98

Liver, effect of CF on, 71

Los Alarnos National Laborato~, 100

Imuisiana

genetic services fhnding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditary conditions and state law in, 202

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

Tay-Sachs disease and carrier screening in, 255, 257

wrongful life claims in, 130

Imuisiana French Acadians, Tay-Sachs disease and carrier

screening in, 254, 255

Lung therapy, 73-75

Lung transplants, 77

Maine

genetic services fimding in, 159

Medicaid reimbursement for genetic services in, 183

Medical Liability Demonstration Project of, 125

Malpractice. See Medical malpractice

Marfan syndrome

health insurance difficulties and, 34, 200

inheritance pattern of, 87

Maryland

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditzuy conditions and state law in, 202,203

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

study of risk perception in, 24, 143

Tay-Sachs carrier screening in Baltimore, 255,256

Tay-Sachs carrier screening of Orthodox Jews in, 256

Massachusetts

genetic services funding in, 159

Medicaid nArnbursement for genetic services in, 183

non-master’ s-level counselors and sickle cell programs in,

155

Tay-Sachs carrier screening of Orthodox Jews in, 256

Master’ s-level counselors. See Genetic counselom

Maternal and Child Health (X4CH) Block Grant

as a focus of congressional options to enhance professional

education and training, 41+2

enactment of, 25, 26, 52, 53

funding for genetic services under, 25,26,53, 158-160

Maternal serum alpha-fetoprotein (MSAFl?)

levels as indicators for Down syndrome or neural tube defects,

16, 143, 144

regulatory class of test kits for, 118

screening and reimbursement under Medicaid, 182-184

screening for, 144, 151

test kits and FDA, 118-119

understanding risks of screening results for, 143

Mayo Medical Laboratories, cost of CF mutation analysis by,

39,216

McCarran-Ferguson Ast of 1945, 175

McGann, John, 194

McGann v. H & HMusic Co,, 194

McGill University, pilot study at, 19, 162

Meckel-Gruber fetus, health insurance difficulties and, 34,200

Meconium ileus, 69,71

Median age of individual with CF, 5,77,78

Median sumival of individual with CF

current, 5, 6, 77

effect of cost-effectiveness of, 225

Medicaid

health care coverage under, 25, 169

reimbursement for genetic services by, 28, 182-184

Medical mpeCtS, 69-79

Medical Device Amendments of 1976 (MDA)

regulation of test kits under, 116-118

see also Food and Drug Administration, U. S.; Safe Medical

Devices Act of 1990

Medical Information Bureau (MB), individual health insurance

and, 174-175

Medical malpractice

inadequate genetic counseling and, 23, 129-131

influence of professional society statements on claims of, 21,

123

standards of CiMt? and, 21, 122

Tay-Sachs carrier screening and, 121
Index ● 295

wrongful birth claims of, 23, 130, 131

wrongful life claims of, 23, 130-131

see also Standards of care

Medical Research Council (MRC)--United Kingdom

CF carrier screening pilot programs funded by, 17, 233

health services research by, 232

role in CF carrier screening of, 232-233

Medicare

clinical laboratory regulation and, 112, 114

health care coverage under, 25, 169

Mendel, Gregor, iii, 87

Michigan

confidentiality of medical information in, 131

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

newborn screening fees as a source of genetic services funding

in, 26, 53

Tay-Sachs carrier screening of Orthodox Jews in, 256

Military Health Services System (MHSS), 170

Minnesota

genetic services funding in, 159

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic semices in, 183

Mississippi

disability statute of, 204

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

Missouri

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditay conditions and state law in, 202

Medicaid reimbursement for genetic services in, 183

Model Eugenics Act, 51

Montana

genetic services funding in, 159

Medicaid reimbursement for genetic semices in, 183

Morocco, Tay-Sachs disease in Jews from, 254

Mucus

changes in as an indicator of CF, 5, 69

glandular secretions of, 69

Multiple sclerosis, as covered by the ADA, 205

Multiplex analysis, 98

Mutations

causing CF, 3, 58, 90, 91, 253

commonly used in CF carrier tests, 58,99, 233,234, 236,239

effects of, 9, 87-88

inheritance patterns of, 86-87

RFLP and, 12, 95

typeS of, 87

see afso Cystic fibrosis mutations

National Academy of Sciences, 1975 report on genetic screening

of, 54

National Association of Insurance Commissioners Insurance

Information and Privacy Protection Model Act, 175

National Cancer Institute, pilot projects for genetic tests and

cancer, 157-158

National Center for Education in Maternal and Child Health, as

a focus of congressional options to improve public

education in genetics, 41

National Center for Human Genome Research (NCHGR)

CF carrier screening pilot studies funded by, 16,52,56, 101,

157-158

CF-related research funded by, 102

development of approach for pilot studies by, 156-157

pilot projects for genetic tests and cancer, 157-158

research on stigmatization and genetics funded by, 29, 191

role in initiating and funding CF carrier screening pilot studies

by, 16,52

see also Ethical, hgal, and Social Issues Prograrn-NIH

National Center for Nursing Research (NCNR)

CF carrier screening pilot study funded by, 16,52,56

CF-related research funded by, 102

development of approach for pilot studies by, 156-157

National Center for Research Resources

CF-related research funded by, 102

joint ELSI program grant funded by, 55

National Cooley’s Anemia Control Act, 52, 261

National Eye Institute (NH), CF-related research funded by, 102

National Genetic Diseases Act, 15,24,25,43,51, 149, 158,255

National Health Service (NHS)--United Kingdom, 231

National Heart, Lung, and Blood Institute (NHLBI), CF-related

research fimded by, 101, 102

National Institute of Allergy and Infectious Diseases (~),

CF-related research funded by, 102

National Institute of Arthritis and Musculoskeletal and Skin

Diseases ( NIAMS), CF-related research funded by, 102

National Institute of Child Health and Human Development

(MCHD)

CF carrier screening pilot study funded by, 16, 52, 56, 101,

157-158

CF-related research funded by, 102

development of approach for pilot studies by, 156-157

National Institute of Dental Research (NIDR), CF-related

research funded by, 102

National Institute of Diabetes and Digestive and Kidney

Diseases (NIDDK)

CF-related research funded by, 101, 102

development of approach for pilot studies by, 156-157

National Institute of General Medical Sciences (NIGMS),

CF-related research funded by, 102

National Institute of Mental Health (NKMH), CF-related research funded by, 102

National Institute of Neurological Disorders and

Stroke (NINDS), CF-related research funded by, 102

National Institutes of Health (NIH)

approval for gene therapy by, 94

CF carrier screening pilot studies funded by, 16,52,56, 101,

156-158

CF-related research funded by, 100-101, 102

collaboration with CFF to fund research of, 102, 103

ELSI program of, 5, 16,55-56

Joint Subcommittee on the Human Genome (DOE) of, 35,206

Workshop on Population Screening for the Cystic Fibrosis

Gene, 21, 146, 150, 155-156,263

see also specific institutes and centers

National laboratories, U. S., 43,98, 100

National Research Council (NRC), 1975 report on genetic
296 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

screening of, 54

National Science Foundation

as a focus of congressional options to improve public

education in genetics, 41

funding for 1975 NRC report and, 54

funding with NIH of ELSI grants, 55

public education in genetics and, 24, 149

National Sickle Cell Anemia Control Act, 52,259

National Sickle Cell Anemia, Cooley’s Anemia, Tay-Sachs, and

Genetic Diseases Act (National Genetic Diseases Act),

15, 24,25,43,51, 149, 158,255

National Society of Genetic Counselors (NSGC), 62, 123,200,

153, 154

National Tay-Sachs and Allied Diseases Association (NTSAD),

257

Native Americans, health care coverage and, 169

Nebraska

genetic services tiding in, 159

Medicaid reimbursement for genetic services in, 183

Negligence. See Medical malpractice

Netherlands, the

frequency of AF508 in, 250

membership in European Concerted Action on Cystic Fibrosis

of, 241

Neurofibromatosis, health insurance difficulties and, 34,200

Nevada

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

New Hampshire

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

New Jersey

genetic services funding in, 159

hereditary conditions and state law in, 202

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

wrongful life claims in, 130

New Mexico

confidentiality of medical information in, 131

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic sewices in, 183

New York

ct-thalassemia carrier screening in Rochester, 260

attitudes toward abortion of families with CF-affected children in Rochester, 127

~-thalassemia carrier screening in Rochester, 261

genetic semices funding in, 159

henxiitary conditions and state law in, 202

Medicaid reimbursement for genetic services in, 183

regulation of clinical laboratories by, 36, 114, 115

regulation of DNA-based tests by, 115

Tay-Sachs carrier screening in New York City, 256

New Zealand, membership in European Concerted Action on

Cystic Fibrosis of, 241

Newborn screening

for CF, 4,50,73

for CF carrier status, 150

in the United Kingdom, 231

State law and, 51

Nixon, President, 51, 259

Non-master’ s-level counselon

NSGC recommendations about, 154

role in genetics, 154-155

use in sickle cell programs, 155

Norns, Jane, 29, 191

North America

correlation of frequency of CF mutations in Europe and, 247

equencies of common CF mutations in, 253

frequency of AF508 in, 253

North Carolina

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic semices in, 183

North Dakota

confidentiality of medical information in, 131

genetic services funding in, 159

Medicaid reimbursement for genetic semices in, 183

Northern Ireland

frequency of AF508 in, 252

membership in European Concerted Action on Cystic Fibrosis

of, 241

see also United Kingdom

Norway, membership in European Concerted Action on Cystic

Fibrosis of, 241

Nurses

1991 OTA survey of, 21,24,33,62, 121, 123, 141, 145, 148,

149, 150, 151, 153, 154, 180, 199-202

Federal support for genetics education of, 41, 155

role in genetics of, 25, 155

Obey, Representative David R., iii, 3

Offke of Pemomel Management, U. S., 28

Office of lkchnology Assessment (OTA)

1986 survey of public attitudes by, 20-21,62-63,94

1989 survey of Fortune 500 and companies with 1,000 or more

employees by, 30, 42, 192

1991 survey of genetic counselors and nurses by, 21,24,33,

62,121,123,141,145,148, 149,150,151,153,154, 180,

199-202

1991 survey of health insurers by, 27-28,31-33,62, 176-179,

180-182, 193-199

congressional issues and options identifkd by, 4045

cost-effectiveness analysis by, 3840, 213-226

number of CF carrier tests in 1992 projected by, 18, 20,61

scope and organization of this report by, 63

terminology used by, 4,49-50

Ohio

genetic semices funding in, 159

Medicaid reimbursement for genetic services in, 183

Tay-Sachs carrier screening in Akron, 256

Oklahoma

genetic services funding in, 159

genetics education, technical assistance, and trainin g filnding

in, 160

Medicaid reimbursement for genetic services in, 183

Omnibus Budget Reconciliation Act of 1981,26,53, 158

Omnibus Budget Reconciliation Act of 1989, 112

Oregon

confidentiality of medical information in, 131
Index ● 2 9 7

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditary conditions and state law in, 202

Medicaid reimbursement for genetic semices in, 183

Pancreas

effect of CF on, 69, 70-71

enzyme replacement therapy related to, 75

insufficiency of enzymes from, 70-71

Participation

cost-effectiveness and assumptions about, 38-40, 218-219,

224

effect on cost-effectiveness of, 40, 224

lessons from past carrier screening programs, 15, 263

Patents. See Intellectual property

Pathology

of CF in gastrointestinal system, 4-5, 70-71

of CF in reproductive system, 71

of CF in respiratory system, 4-5, 69-70

of CF in skeletal system, 72

of CF in sweat glands, 71

Pemsylvania

CF screening of newborns in, 73

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Percutaneous umbilical blood sampling, prenatal analysis using,

147

Permanence Medical Group, Inc., privately funded pilot study at,

19, 162-163

Personnel. See Education; Genetic services; Licensing; Training

Pharmaceuticals

costs of CF-related, 38, 215

used to treat CF, 73-74, 75

Phenylketonuria

1975 report of the NRC, 54

1983 report of the President’s Commission for the Study of

Ethical Problems in Medicine and Biomedical and

Behavioral Research and, 54

health insurance difficulties and, 34,200

inheritance pattern of, 88

Physical therapy. See Chest physical therapy

Pilot studies

congressional options to facilitate future, 43

federally funded, 16, 18,52, 101, 157-158, 163

in the United Kingdom, 17, 233-239

NH-I development of, 156-157

privately funded, 16, 19, 160-163

Planned Parenthood of Southeastern Pennsylvania v. Casey,

45, 127

Poland

fi-equency of AF508 in, 251

membership in European Concerted Action on Cystic Fibrosis

of, 241

Polymerase chain reaction (PCR)

DNA amplification using, 12,95,96,97

intellectual property protection and, 39, 44, 217

quality assurance and, 111

Population carrier screening. See Cystic fibrosis carrier screening; Population target

Population target

cost-effectiveness and assumptions about, 39-40, 218, 219

effect on cost-effectiveness of, 224

lessons from past carrier screening programs, 15,263-264

potential and Likely, 16,58, 150-152

variation among CF carrier screening pilot studies, 15-16, 18,

19, 157-158, 160-162

variation among U.K. CF carrier screening piIot studies, 17,

238,239, 242

Portugal

frequency of AF508 in, 251

membership in European Concerted Action on Cystic Fibrosis

of, 241

Practice standards

alternative approach in Maine to set, 125

congressional role in setting, 43

role of Agency for Health Care Policy and Research, 43

see afso Standards of care

Preexisting conditions

genetic conditions as, 31, 195

carrier status as, 31, 195

Preferred provider organization (PPO), 170, 171

Pregnancy

CF mutation analysis and, 16, 151

stigmatization of, 189

see also Prenatal testing

Pregnancy termination. See Abortion

Prenatal testing

anxiety and, 148, 151

CF mutation analysis and, 16,58,60,147-148, 151-152,234,

236

decisions about abortion following, 45, 127,265

health insurers’ economic analysis of, 178-179

reimbursement for CF, 27, 181-182

President’s Cotision for the Study of Ethical Problems in

Medicine and Biomedical and Behavioral Research

1983 report on genetic screening, 52,54,63

1983 report on health care access, 193

principles of confidentiality in 1983 report of, 63, 128-129

value of CF carrier screening and, 45, 213, 226

Prices. See Costs

Privacy. See Confidentiality

Professional capacity, impact of increased number of genetic

tests on, 24-25, 152-155

Professional societies

interest in CF carrier screening of, 21, 56

policy statements on CF carrier screening of, 123

role in clinical laboratory quality assurance of, 36, 111,

114-116

role in genetic services quality assurance of, 23, 121-122, 123

Proficiency testing, 113, 115-116

Prognosis

current, 77-78

genotypic correlation with, 91

nutritional status and, 5, 71

respiratory difficulties and, 4-5, 69-70, 71

Program

for ct-thalassemia carrier screening, 260

for ~-thalassemia carrier screening, 261-263

for sickle cell anemia screening, 155,258-259

for Tay-Sachs disease carrier screening, 231,255-257

OTA deftition as applied to CF carrier screening, 4,50

Proteins, 86

Public attitudes, toward genetic tests, 20-21,62-63, 143, 190
298 . Cystic Fibrosis and DNA Tests: Irnplieations of Carrier Screening

Public education

as a factor affecting utilization of CF carrier tests, 20, 24

importance for avoiding stigmatization, 15, 29, 149-150, 163,

192

lessons from past carrier screening programs, 15,24,152,264

see also Education

Public health

genetic screening and, 43,57

professionals and genetic services, 25, 155

Public Health Service Act

Title VII as a focus of congressional options to enhance

professional education and training, 42

Title VIII as a focus of congressional options to enhance

professional education and training, 42

Title X, 45, 127

Public opinion. See Public attitudes

Puerto Rico, genetic services fimding in, 159

Quality assurance

as a factor affecting utilization of CF carrier tests, 20, 35-37

of clinical laboratories, 35-37, 111-116

of DNA test kits, 37, 111, 116-120

of genetic semices, 22-23, 111, 120-132

see also Clinical Laboratory Improvement Amendments of

1988; Food and Drug Administration, U. S.; Genetic

services

Quality control, 111

Recombinant DNA Advisory Committee (RAC)-NIH, 94

Regulation

of BC/BS pkms, 25, 171

of clinical laboratories, 35-37, 111-116

of HMos, 25, 171-172

of insurance contracts, 175

of insuring entities, 25, 175

of medical devices, 37, 116-120

of self-funded employee benefit plans, 27, 171

Rehabilitation Act of 1973,204

Reimbursement

CF carrier tests and health insurers’ approaches to, 27,

179-182

experience of genetic counselors and nurses with, 180

for CF carrier tests and willingness to be screened, 27, 180,

181-182

genetic services and Medicaid, 28, 182-184

private sector, 27-28, 179-182

public sector, 28, 182-184

see also Financing

Replication

DNA, 85-86,88

PCR and, 97

Reproductive decisionmaking

as fundamental value of CF carrier screening, iii, 45, 54

cost-effectiveness and assumptions about, 39-40, 219-220

effect on cost-effectiveness of, 40, 223-224

Reproductive system, effect of CF on, 71

Research

CFF and, 102-103

finding for CF-related basic, 3-4, 100-103

Howard Hughes Medical Institute, 100, 103

dated to clinical assessments of CF carrier screening, 15-16,

18, 19,52, 101, 156-158, 160-162

see also HumarI Genome Project

Respiratory system

effect of CF on, 3, 4-5, 69-70

prognosis related to severity of problems in, 69-70

Restriction enzymes, 12,95

Restriction fragment length polymorphism (RFLP) analysis

localization of CF gene using, 90,96

usefulness in testing relatives of individuals with CF, 12,

145-146, 148

Reverse dot blot, 12,98,99

Rhode Island

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Ribonucleic acid, 8,86,89

Rigshospitalet<openhagen, 238, 239

Risk

CF carrier, 14,58,90, 145

classification and individual health insurance, 25, 30-31, 172,

174, 193-194

genetic counseling and communicating, 22, 126-127

insurers’ attitudes toward genetic, 193-197

negative result and adjusted CF carrier, 146

of child with CF after screening, 59, 146-147

of child with CF if family history exists, 145

understanding, 22, 24, 142-143

Robotics. See Automation

Roche Biomedical Laboratories, privately funded pilot study at,

19, 162

Roche Molecular Systems, PCR patent rights and, 44, 217

Roe v. Wade

recent Supreme Court decisions and, 45, 127

wrongful birth claims and, 130

Royalties. See Intellectual property

Rust v, Sullivan, 45, 127

Safe Medical Devices Act of 1990 (SMDA)

application to CF mutation test kits, 42-43, 118-120

classification of devices under, 37, 117-118

congressional options for, 42

regulation of in vitro diagnostics under, 42, 116-118

see also Food and Drug Admints- tration, U. S.; Medical Device

Amendments of 1976

Saint. See St.

Salty taste, as an indicator of CF, 49, 69,71

Sardinia, Italy

fl-thalassemia carrier screening program in, 261-262

frequency of AF508 in, 250

Savings

assumptions affecting, 3940, 222-226

calculation of base case and alternative scenario, 222

welfare standpoint and, 38, 214, 226

Scotland

CF carrier screening pilot program in, 17,233,234,236-237

frequency of AF508 in, 231,252

membership in European Concerted Action on Cystic Fibrosis

of, 241

see aZso United Kingdom

screening

definition used in OTA report of genetic, 4,50

see also fhh.lassemia; Cystic fibrosis carrier screening;

Cystic fibrosis carrier testing; Sickle cell anemia; Tay -

Sachs disease; Testing
Index ● 299

Secretory leukocyte protease inhibitor, 76

Self-funded employers

assessment of health insurance risk of potential employees by,

192

exemption from contributing to high-risk pools for, 170

exemption from State insurance regulation under, 27, 171

health benefit plans of, 171

health care benefit changes and, 27, 194

see also Employee Retirement Income Security Act of 1974

Sensitivity

cost-effectiveness and assumptions about test, 218

effect on cost-effectiveness of test, 224, 225

of CF mutation analysis, 10, 13, 58-59

Sequencing. See DNA sequencing

Serous glands, increased salt content in secretions of, 69

Severe combined immune deficiency, gene therapy for, 94

Sicily, sickle cell mutation in, 258

Sickle cell anemia

1983 report of the President’s Commission for the Study of

Ethical Problems in Medicine and Biomedical and

Behavioral Research and, 54

congressional interest in, 51-52, 259

genetics of, 15,88,257, 258

manifestations of, 257-258

screening programs for, 15, 155, 258-259

State laws on, 202, 258-259

stigmatization and screening for, 192, 259

Single-gene counselors. See Non-master’ s-level counselors

Skeletal system, effect of CF on, 72

Social Security Act, Title V of the, 158

Social workers, role in genetic services of, 25, 155

South Africa

membership in European Concerted Action on Cystic Fibrosis

of, 241

Tay-Sachs carrier screening in, 255

South Carolina

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

South Dakota

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

Southeast Asians

ct-thalassernia and stillbirths among, 260

a-thalassemia screening in U. S., 260

~-thalassemia carrier screening of, 262-263

~-thalassemia mutations in U. S., 259

Southern blot, 95, 96

Southern transfer, 95, 96,98

Spain

frequency of AF508 in, 251

frequency of AF508 in Balearic Islands, 251

frequency of AF508 in Basque country, 251

frequency of AF508 in Canary Islands, 251

frequency of AF508 in Central/Southern, 251

membership in European Concerted Action on Cystic Fibrosis

of, 241

Special Projects of Regional and National Significance

(SPRANS), 26,53, 160

St. Bartholomew’s Hospital (Bart’s)-Imndon, CF carrier

screening pilot program at, 17, 238, 239

St. Mary’s Hospital Medical School—I.mdon

CF carrier screening pilot program at, 17, 238-239

MRC funding for CF carrier screening pilot program at, 233

St. Vincent’s Medical Center, cost of CF mutation analysis at,

39, 216

Standards of care

alternative approach in Maine to set, 125

as a factor affecting utilization of CF carrier tests, 20-23

congressional options for, 40, 43

factors affecting, 21, 121-124

medical malpractice and, 21, 122

professional societies and, 21, 123

States

abortion laws and, 45, 127

confidentiality of genetic information and, 22, 128, 131

eugenics laws and, 51

funding for genetic services by, 26,52,53, 158-160

hereditary conditions and laws of, 202

high-risk insurance pools and, 25, 169, 170

licensing of genetics personnel by, 23, 120

Medicaid programs of, 25, 169

Medicaid reimbursement for genetic procedures by, 28,

182-184

newborn screening laws of, 51

regulation of health insurance by, 25, 171, 172, 175

role in quaIity assurance for clinical laboratories of, 36, 113,

114

wrongful birth and wrongful life claims in, 23, 130

see also individual States

Stigmatization

as a factor affecting utilization of CF carrier tests, 28-35

avoiding, 29, 192

concerns stemming from CF carrier screening, 28, 60,

189-191

empirical studies of genetic, 29, 191-192

genetic screening and, 52

of carrier status, 28-29, 189-192

of pregnancy, 16, 189

reproductive-related, 28, 190-191

sickle cell screening and, 259

Tay-Sachs carrier screening and, 190, 191

see also Discrimination

Strategies. See Population target

Supreme Court, U.S.

i14cGann v. H & H Music Co., 194

Planned Parenthood of Southeastern Pennsyhrania v. Casey,

45, 127

Roe v. Wade, 45, 127

Rust v. Sulli~an, 45, 127

Survey

by OTA of American public attitudes toward genetic tests and

gene therapy, 20,62-63,94

by OTA of Fortune 500 companies of other employers, 30,42,

192

by OTA of genetic counselors and nurses in genetics, 21,24,

33,62, 121, 123, 141, 145, 148, 149, 150, 151, 153, 154,

180, 199-202

by OTA of health insurers, 26-33, 62, 176-180, 193-199

Survival, 77-78

Sweat glands, effect of CF on, 69, 71

Sweat test, 4, 72

Sweden, membership in European Concerted Action on Cystic
300 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Fibrosis of, 241

Switzerland

frequency of AF508 in, 251

membership in European Concerted Action on Cystic Fibrosis

of, 241

Target population. See Population target

Tay-Sachs disease

1983 report of the President’s Commission for the Study of

Ethical Problems in Medicine and Biomedical and

Behavioral Research and, 54

California court ruling and standard of care for carrier

screening of, 121-122

carrier frequency of, 121

carrier screening for, 15, 231, 255-257

congressional interest in, 52

genetics of, 15,88,254-255

manifestations of, 254

State law against discrumination for, 202

stigmatization and carriers for, 190, 191

Tennessee

genetic services funding in, 159

genetics education, technical assistance, and training fimding

in, 160

Medicaid rvirnbursement for genetic services in, 183

Tay-Sachs carrier screening of Orthodox Jews in, 256

Terminology, used in OTA report, 4,49-50

Test kits

congressional options for regulation of, 40, 4243

importance to CF carrier screening of, 37, 132

regulation of DNA, 37, 116-120, 132

~gulatory future of CF mutation, 37, 118-120, 132

lksting

definition used in OTA report of genetic, 4,49-50

see also ~-thalassemia; Cystic fibrosis carrier screening;

Cystic fibrosis carrier testing; Screening; Sickle cell

anemia; Tay-Sachs disease

Tests

automation of, 37-38, 98-100

CF functional tests, 9,93

to detect CF mutations, 9-11,58-59, 95-100

to detect genetic disorders, 85

to diagnosis CF, 72-73

BXas

genetic services fimding in, 159

McGann v. H & H Music Co., 194

Medicaid reimbursement for genetic services in, 183

Thalassemia. See cAmlassemia; f3-thalassemia

Therapy

costs of, 38, 214-216

current CF, 5, 73-77

future CF, 6,76,93

impact in improvements on cost-effectiveness of new, 213,

225

see also Gene therapy; Prognosis; Treatment

Training

as a factor affecting utilization of CF carrier tests, 20, 24-25

congressional issues and options for professional education

and, 40,4142

lack of Federal funding for genetic services-related, 25,52

professional continuing education and, 24, 154

SPRANS funding for, 26, 160

see also Education

Transcription, 8,86,89,92

Translation, 8, 86,89,92

Treatment

chest physical therapy, 5, 76

costs of, 38, 214-216

digestive therapy, 75

effect on costdfectiveness of costs of, 213

lung therapy, 73-75

transplants, 77

see also Gene therapy; Prognosis; Therapy

Trends

in number of nonresearch carrier tests, 61

in number of research carrier tests, 61

in therapy for CF, 76, 93, 94

in total number of carrier tests, 18, 20, 61

‘Iiherculosis, compulsory sterilization and, 51

‘lMane University, 257

‘llrkey

frequency of AF508 in, 251

sickle cell mutation in, 258

Tuer’s syndrome, health insurance difficulties and, 34,200

Ultrasound, reimbursement under Medicaid for, 28, 182-184

Underwriting, health insurance and, 25-26, 32, 172, 174, 176,

193

Union of Soviet Socialist Republics (USSR; former)

frequency of AF508 in, 251

frequency of AF508 in Moscow/Odessa, 251

membership in European Concerted Action on Cystic Fibrosis

of, 241

United Kingdom

CF carrier screening in the United States compared to, 17,

241-242

CF carrier screening pilot programs in, 17,233-239

eugenics movement in, 51

Fragile X screening proposed in, 265

iiequency of AF508 in, 251

frequency of AF508 in England, 231,251

frequency of AF508 in Northern Ireland, 252

frequency of AF508 in Scotland, 231,252

genetic services in, 231-233

MSAFP screening in, 119

outlook for CF carrier screening in, 240-241

public attitudes toward, 17,239

role of CF trust in CF carrier screening, 233-238

role of MRC in CF carrier screening, 232-233

United States

cc-thalassemia carrier screening in, 260

j3-thalassemia carrier screening in, 261

eugenics movement in, 51

frequency of common CF mutations in, 253

frequency of AF508 in, 58,253

sickle cell screening in, 258-259

Tay-Sachs carrier screening in, 255-257

see also Cystic fibrosis; Cystic fibrosis carrier screening;

Federal Government; States

University Hospital of Wales<ardiff, CF carrier screening

pilot program at, 17,233-234,235,237,239

University of California, Los Angeles (UCLA), School of

Medicine, NIH-funded pilot study at, 18, 158

University of Miami School of Medicine, 256
Index Q 301

University of Minnesota, cost of CF mutation analysis at, 39,216

University of North Carolina

cost of CF mutation analysis at, 39, 216

NIH-funded pilot study at, 18, 157

University of Padua-Italy, 238, 239

University of Pennsylvania

cost of CF mutation analysis at Hospital of, 39, 216

NIH-funded pilot study at, 18, 158

University of Rochester, NIH-funded pilot study at, 18,157-158

University of Vienna-Austria, 239

Utah

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

Vanderbilt University, NH-tided pilot study at, 18, 157

Vermont

genetic services funding in, 159

Medicaid reimbursement for genetic services in, 183

Virginia

genetic services funding in, 159

hereditary conditions and state law in, 202

mandato~ reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

sterilization law of, 51

Vivigen, Inc.

cost of CF mutation analysis by, 39, 216

privately funded pilot study and, 19, 162-163

Wales

CF carrier screening pilot program in, 17,233-234,235,237

membership in European Concerted Action on Cystic Fibrosis

of, 241

see also United Kingdom

Walker Larnpley, Bree, 29, 191

Washington

genetic services funding in, 159

genetics education, technical assistance, and training finding

in, 160

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

wrongful life claims in, 130

West Germany (former). See Germany

West Virginia

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic sewices in, 183

Western General Hospital-Edinburgh

CF carrier screening pilot program at, 17,233,234,236,238,

239

MRC funding for CF carrier screening pilot program at, 233

Wisconsin

CF screening of newborns in, 4,50,73, 150

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

hereditary conditions and state law in, 202

mandatory reporting of birth defects in, 128

Medicaid reimbursement for genetic services in, 183

World Health Organization, 260,262

Wrongful birth

claims and compensation, 23, 130, 131

definition of, 130

State statutes on, 130

Wrongful life

claims and compensation, 23, 130, 131

definition of, 130

State statutes on, 130-131

Wyoming

genetic services funding in, 159

genetics education, technical assistance, and training funding

in, 160

Medicaid reimbursement for genetic services in, 183

X chromosome

in females, 85

in males, 85

role in Fragile X syndrome, 265

role in X-linked inheritance, 88, 89, 90

Y chromosome

genetic disease and, 88

in males, 85

Yellowstone National Park, 97

Yugoslavia (former)

frequency of AF508 in, 252

frequency of AF508 in Macedonia, 252

frequency of AF508 in Slovenia, 252

frequency of AF508 in Southern, 252

membership in European Concerted Action on Cystic Fibrosis

of, 241
Other Related OTA Reports

● Artificial Insemination Practice in the United States: Summary of a 1987 Survey

OTA-BP-BA-48, August 1988; 112p.

NTIS order #PB89-139903

. Biotechnology in a Global Economy

OTA-BA-494, October 1991; 282p.

GPO stock # 052-003 -01258-8

● Genetic Monitoring and Screening in the Workplace

OTA-BA-455, October 1990; 262p.

NTIS order #PB91-105940

● Genetic Witness: Forensic Uses of DNA Tests

OTA-BA-438, July 1990; 204p.

NTIS order #PB90-259110

● Healthy Children.” Investing in Our Future

OTA-H-344, February 1988; 310 p.

NTIS order #PB88-178454

• Human Gene Therapy

OTA-BP-BA-32, December 1984; 116p,

NTIS order #PB85-206076

● Infertility.” Medical and Social Choices

OTA-BA-358, May 1988; 402p.

NTIS order #PB88-19&164

● Medical Monitoring and Screening in the Workplace.” Results of a Survey

OTA-BP-BA-67, September 1990; 96p.

GPO stock #052-003-01255-3

. Mapping Our Genes—The Genome Projects: How Big, How Fast?

OTA-BA-373, A@ 1988; 232p.

NTIS order #PB88-212402

● Medical Testing and Health Insurance

OTA-H-384, August 1988; 224 p.

NTIS order #PB89-1 16958

● New Developments in Biotechnology: Public Perceptions of Biotechnology

OTA-BP-BA-45, May 1987; 136p.

NTIS order #PB87-207544

● Technologies For Detecting Heritable Mutations in Human Beings

OTA-H-298, September 1986; 156 p.

NTIS order #PB87-140158

NOTE: Reports are available from the U.S. Government Printing Office, Superintendent of Doeurnents, Dept. 33, Washington, DC

20402-9325, (202) 783-3238, and/or the National Technical Information Service, 5285 Port Royal Road, Springfield, VA

22161-0001, (703) 4874650.