THE CHANGING 

MORAL FOCUS OF 

NEWBORN SCREENIN

THE CHANGING 

MORAL FOCUS OF 

NEWBORN SCREENIN

An Ethical Analysis by 

the President’s Council on Bioethics 

Washington, DC 

December 2008 

www.bioethics.gov 

LETTER OF TRANSMITTAL TO THE PRESIDENT........................... 

MEMBERS OF THE PRESIDENT’S COUNCIL ON BIOETHICS ....... 

COUNCIL STAFF ............................................................................... 

PREFACE ........................................................................................... 

INTRODUCTION ............................................................................... 

CHAPTER ONE: NEWBORN SCREENING TODAY ........................ 

I. The Practice of Newborn Screening .................................... 

A. Education..................................................................... 

B. Screening ...................................................................... 

C. Follow-up and Diagnosis........................................... 

D. Treatment and Evaluation......................................... 

II. Public Policy and Newborn Screening ................................ 

CHAPTER TWO: THE CHANGING PRINCIPLES AND PRACTICE

OF NEWBORN SCREENING............................................................. 

I. The Classical Principle: Screen Only If You Can 

 Effectively Treat..................................................................... 

II. Newborn Screening and the ACMG’s Expanded 

 Uniform Panel ......................................................................... 

A. Reactions to the ACMG Report............................... 

B. The Core or Primary Conditions.............................. 

C. The Secondary Conditions ........................................ 
g

 Screening Panel........................................................................ 

CHAPTER THREE: THE FUTURE OF NEWBORN SCREENING..... 

I. Newborn Screening at the Dawn of the Genomic Era..... 

II. The Case for Newborn Profiling .......................................... 

A. The Logic of Personalized Medicine and 

 Technological Progress .............................................. 

B. The Benefits of Biobanking ...................................... 

C. The Psychosocial Consequences of Testing 

 Positive: A Silver Lining?........................................... 

D. The Support of Parents and Advocacy 

Groups.......................................................................... 

III. The Case for Caution.............................................................. 

A. “Personalized Medicine” in the Traditional 

 and Increasingly Rare Sense ..................................... 

B. Doubts About the Power of Genomic 

Medicine ....................................................................... 

C. Newborn Profiling and the Problem of Risks 

and Benefits ................................................................. 

D. Ownership of Genetic Information and the 

Challenge of Informed Consent ............................... 

E. Genetic Disease and Human Difference................. 

F. Newborn Screening, Genomic Medicine, 

and Eugenics................................................................ 

G. Genetic Information and the Problem of 

Self-Knowledge........................................................... 

IV. On the Necessity and the Limits of Speculation................ 
II. A Two-Tiered Approach to Newborn Screening............... 

A. The Massachusetts Model.......................................... 

B. The Future of Screening in Massachusetts ............. 

III. Combining the ACMG’s Recommended Panel and 

 a Two-Tiered Approach......................................................... 

IV. An Ethical Framework for the Ongoing Expansion of 

 Newborn Screening: A Recommendation by the 

 President’s Council on Bioethics .......................................... 

PERSONAL STATEMENTS ................................................................ 

Floyd E. Bloom, M.D., and 

Michael S. Gazzaniga, Ph.D. ................................................ 

Jean B. Elshtain, Ph.D. .......................................................... 

Gilbert C. Meilaender, Ph.D. ................................................ 

Carl E. Schneider, J.D. .......................................................... 

BIBLIOGRAPHY................................................................................. 

\[

ix

1425 New York Avenue, NW, Suit

Washington, DC 

Decembe

The President 

The White House 

Washington, DC 

Dear Mr. President: 

With this letter, I am transmitting a white paper entitled The 

ing Moral Focus of Newborn Screening: An Ethical Inquiry by the Pr

Council on Bioethics. 

Nearly four million newborns undergo genetic screening eve

in the United States. Yet, the process of genetic screening 

ethical implications are not well understood by their parents. 

discussion and education about recent changes in public poli

screening techniques is insufficient for parents to make inf

choices. One aim of this white paper is to provide the backg

information every parent needs in order to understand the 

and to make informed choices. 

Most states have mandatory genetic screening programs fo

born babies. Until recently such screening was limited to d

that were well understood and for which effective treatment

available. Now, however, most mandatory screening program

test for diseases that are not well understood and for which t

no available treatment. Some believe this change is ethically 

able because much knowledge of little understood diseases co

gained and lead eventually to treatment and cure. 

This white paper describes how the change in policy to i

screening for untreatable as well as treatable diseases came 
no current treatment are outweighed by the potential harms. 

harms will be accentuated once new DNA technologies m

possible to expand screening to target additional diseases 

detect disease susceptibility as well. But the Council also ac

edges that the gains in biomedical knowledge from exp

screening programs should not be ignored. 

Therefore, the Council recommends that the states mandat

born screening only for diseases that meet traditional c

including the availability of an effective treatment. But the sta

encouraged to implement pilot studies for newborn screen

conditions that do not meet the traditional criteria. Participa

these pilot studies should require the voluntary, informed c

of the infant’s parents. 

In this way, the present benefits of newborn screening can b

mized in an ethical way, and the future benefits of new tech

to expand our knowledge of untreatable diseases will be fac

in an ethically sensitive way. 

Sincerely yours, 

Edmund D. Pellegrino, M.D. 

Chairman 
xi

Professor Emeritus of Medicine and Medical Ethic

Adjunct Professor of Philosophy, Georgetown Unive

FLOYD E. BLOOM, M.D. 

Professor Emeritus in the Molecular and Integrative N

science Department at The Scripps Research Institute 

BENJAMIN S. CARSON, SR., M.D. 

The Benjamin S. Carson, Sr., M.D., and Dr. Evelyn 

R.N., Professor of Pediatric Neurosurgery, Director 

diatric Neurosurgery, and Professor of Neuros

Oncology, Plastic Surgery, and Pediatrics, Johns H

Medical Institutions 

REBECCA S. DRESSER, J.D., M.S. 

Daniel Noyes Kirby Professor of Law and Profes

Ethics in Medicine, Washington University, St. Louis 

NICHOLAS N. EBERSTADT, PH.D.

Henry Wendt Chair in Political Economy, American 

prise Institute 

JEAN B. ELSHTAIN, PH.D. 

Laura Spelman Rockefeller Professor of Social and P

Ethics, University of Chicago, and Thomas and D

Leavey Chair in the Foundation of American Fre

Georgetown University 

DANIEL W. FOSTER, M.D. 

John Denis McGarry, Ph.D., Distinguished Chair in 

tes and Metabolic Research, University of 

Southwestern Medical Center, Dallas, TX 
James Madison Program in American Ideals and I

tions, Princeton University 

ALFONSO GÓMEZ-LOBO, DR. PHIL. 

Ryan Family Professor of Metaphysics and Moral P

phy, Georgetown University 

WILLIAM B. HURLBUT, M.D.

Consulting Professor, Neurology and Neurologic

ences, Stanford Medical Center, Stanford University 

DONALD W. LANDRY, M.D., PH.D. 

Professor of Medicine, Director of the Division of E

mental Therapeutics, and Chair, Department of Me

Columbia University 

PETER A. LAWLER, PH.D. 

Dana Professor and Chair of the Department of G

ment and International Studies, Berry College 

PAUL R. MCHUGH, M.D. 

University Distinguished Service Professor of Psyc

The Johns Hopkins University School of Medicine 

GILBERT C. MEILAENDER, PH.D. 

Richard and Phyllis Duesenberg Professor of Christia

ics, Valparaiso University 

JANET D. ROWLEY, M.D. 

Blum-Riese Distinguished Service Professor of Medic

Molecular Genetics and Cell Biology, and of Human 

ics, Pritzker School of Medicine, University of Chicag
versity of Michigan 

\[

xv

Judith E. Crawford Thomas W. Merrill, Ph

Administrative Director Senior Research Analyst 

Samuel J. Crowe, Ph.D. David G. Miller, Ph.D. 

Deputy Director Senior Research Analyst 

Diane M. Gianelli Marti Patchell 

Director of Communications Special Assistant to the 

 Chairman 

Ginger Gruters 

Research Assistant Joseph A. Raho 

 Research Assistant 

Emily L. Jones 

Executive Administrator Alan Rubenstein 

 Senior Consultant 

Audrea V. Medina 

Information Technology Adam Schulman, Ph.D

Specialist Senior Research Consult

\[

xvii

The Changing Moral Focus of Newborn Screening is a white paper 

President’s Council on Bioethics. The Council was establish

November 28, 2001, to advise the President on bioethical 

related to advances in biomedical science and technology. I

nection with its advisory role, the Council undertakes funda

inquiry into the human and moral significance of developm

biomedical and behavioral science and technology, with the 

fostering greater understanding and public discussion of bio

issues. 

The subject of this white paper is a type of genetic screening 

widely practiced in the United States—and yet little unde

especially by the parents of the nearly four million newborn

are screened every year. In the last few years, both the practi

the moral focus of newborn screening have begun to chang

in ways that are little understood or publicly discussed. W

hope of promoting discussion and understanding of these ch

among policymakers and the public at large, the Council und

the inquiry that now culminates in the publication of this wh

per. 

The origins of this inquiry date back to December 2005, wh

Council began to consider the topic of children and bioeth

September 2006, the Council also took up the topic of ethica

in genetic research and technology. This white paper began 

shape at the confluence of these two broader streams of inq

reflects a careful study of the published literature on the ethic

icy dimensions, and technologies of newborn screening. Th

and arguments presented herein were initially developed in w

papers authored by the Council staff and in discussions amo

Council members themselves. 
Genome Research Institute; Norman Fost of the University o

consin School of Medicine and Public Health; Kathy H

director of the Genetics and Public Policy Center; Michael S

son, executive director of the American College of M

Genetics; and Nancy Wexler, president of the Hereditary D

Foundation. (Transcripts of their remarks are available on

www.bioethics.gov.) The Council extends its thanks to thes

viduals and to Michele A. Lloyd-Puryear, chief of the G

Services Branch of the Maternal and Child Health Bureau 

Health Services and Resources Administration, U.S. Departm

Health and Human Services, and Kevin Fitzgerald, the 

Lauler Professor of Catholic Health Care Ethics at Georg

University, who met with the Council staff to discuss ethical 

confronting the practice of newborn screening today. 

Finally, the Council is grateful to the following experts for the

ingness to read and offer criticism of earlier drafts of porti

this white paper: Duane Alexander, Jeffrey R. Botkin, Wylie 

of the University of Washington, Ellen Wright Clayton of V

bilt University Law School, Thomas Murray of The H

Center, Lainie Friedman Ross of the University of Chicag

Benjamin S. Wilfond of the University of Washington Sch

Medicine. 

\[
1

What ethical principles should guide the practice of newborn screenin

United States? That question is the starting point for this white 

by the President’s Council on Bioethics. It has been a serious 

tion since newborn screening began over four decades a

recent years, however, it has taken on new urgency in light 

nificant and ongoing changes in the practice of newborn scre

In this white paper, the Council analyzes these changes an

ethical implications. 

The great majority of babies born in the United States eac

undergo screening soon after birth to identify genetic defec

could cause serious illness if left undetected and untreated. Th

is to detect diseases as early as possible so that timely, ef

treatment can be initiated even before the onset of sympto

most states, newborn screening is now mandated by law. The 

ber of conditions screened for by state health departmen

expanded considerably since the 1960s, when microbiologist 

Guthrie invented the heel-stick blood test for phenylket

(PKU). In the United States today, almost all infants are scree

birth for between thirty and fifty genetic disorders, depend

the screening program of the state in which they are born. 

approximately four million babies screened each year, about 

are identified as having serious heritable disorders, most of 

are, in varying degrees, amenable to treatment.2 

Newborn screening has produced undeniable benefits: for ex

PKU—which causes severe, irreversible mental retardation 

                                                      

1 More than ninety-eight percent in 2008, according to the Centers for 

Control and Prevention’s Division of Laboratory Sciences. See www.cdc.g

nceh/dls/newborn.htm. 

2 Ibid. 
gy 

with a daily dose of thyroid hormone; newborn screening fo

initiated in the 1970s, now detects over 1,000 cases of CH 

United States each year. In the wake of these and other ac

ments, more and more disorders have been added to 

mandated newborn screening programs. Today, we routinely 

infants for dozens of rare genetic disorders, including some 

medical implications are not clearly understood and for which 

tive treatments are not yet available. 

Traditionally, a population screening program (whether for c

or for adults) has been considered justifiable only if the ta

condition is an important health problem, whose natural his

well-understood, and whose symptoms are amenable to early 

vention and effective treatment. On this view, the obj

screening is to discover those among the apparently well who 

fact suffering from disease, in order to initiate timely and ef

treatment. Accordingly, the mere availability of a reliable test 

not justify routine screening for a condition, unless such scr

could be shown to provide direct medical benefit to those wh

positive for the condition. In short, for more than forty ye

moral focus of newborn screening has been what is good for the 

As more and more disorders have been added to state ne

screening programs, however, the traditional ethical princip

screening have been called into question. Some have argued t

central criterion of direct medical benefit to the infant need 

strictly satisfied in order to justify routine screening for a con

according to this view, a broader conception of benefit—including 

fits to the family and to society at large as well as indirect ben

the child—justifies screening even for conditions that are 

understood or that do not, as yet, have an effective treatmen

ers have argued that all (or almost all) conditions that c

detected should be screened for at birth—reasoning tha
gyy 

The aim of the present white paper is to foster public awaren

the practice of newborn screening, the ethical principles tha

guided it until now, and the ethical problems posed by its c

and future expansion. The white paper consists of four chapt

the first chapter, we describe the current practice of newborn s

ing in the United States: how a blood sample is taken from 

infant at birth, how the blood is tested for heritable disorde

what is done with the information gleaned from those tes

also identify some of the ethical challenges that confront us 

try to reap the benefits of newborn screening while minimiz

harms. Finally, we explain the public policies that shape the p

of newborn screening in the United States. In the second chap

explain the ethical principles that have guided the practice o

born screening for the past forty years, and we consider w

those ethical principles have been altered or abandoned by th

regime of expanded newborn screening that is currently 

adopted by most states. In the third chapter, we attempt to en

the future of newborn screening, examining the ethical impli

of the vast expansion of newborn screening that can be antic

as the age of personalized genomic medicine advances. Fin

the fourth chapter, we take up the urgent question of wheth

states should have mandatory screening programs (as mo

rently do), elective programs, or some combination of the tw

close this chapter and the white paper as a whole by recomm

an ethical framework for a sound newborn screening policy 

United States—a framework that we believe to be not only 

priate for the present phase of newborn screening but also v

for addressing future medical and technological advances in 

born screening. 

\[



5

NEWBORN SCREENING TODAY 

ewborn screening in the United States today is a co

public health endeavor that touches the lives of 

every one of the four million babies born in the c

each year. In this chapter we offer an account of the basic f

of newborn screening as it is practiced in the United States. W

trace the origins and describe the current practice of ne

screening, noting some of the challenging aspects of it tha

ethical questions. Then, we briefly describe the state and 

policies pertaining to the practice of newborn screening. 

I. The Practice of Newborn Screening 

Screening is a public health initiative that surveys an entire p

tion (or sub-population) for evidence of an illness before it e

symptoms. The purpose of screening is to identify those amo

apparently well who are suffering from (or who will likely de

a disease and who are likely to benefit from early detection a

tervention.1

 Because screening is applied to the healthy and t

alike, the screening assay must be both sensitive—it should i

all or almost all cases of disease—and specific—it should mi

the number of false positives, i.e., of healthy individuals w

incorrectly identified as having the disease. When screening f

disorders in large populations, it is all but inevitable that 

healthy individuals will initially test positive for the disease. B

                                                      

1 Screening of populations is different from testing of individuals; an in

patient who exhibits certain symptoms of illness will typically undergo di

testing to ascertain the cause and the severity of the illness. 

N
y 

and chromosomes.3 Newborn screening is applied to the 

population shortly after birth. Genetic screening at other sta

life is also possible, but is generally practiced more selectively 

there is a perceived need. For example, preimplantation gen

agnosis (PGD) involves screening human embryos before t

to a woman’s uterus after in vitro fertilization; prenatal scr

(e.g., by amniocentesis) looks for genetic defects in the fetu

to birth; post-infancy screening is applied to children in th

after birth; carrier screening (at any stage of life, but espec

prospective parents) is used to identify healthy people who 

one copy of a defective gene that, if present in two copies, 

cause an illness.4

 

Newborn screening began in the United States in the early 

after American microbiologist Robert Guthrie developed a t

phenylketonuria (PKU), an inborn error of metabolism that

untreated, causes severe mental retardation. Guthrie’s simple

tive test for PKU required absorbing a drop of the infant’s 

on a piece of filter paper. During the 1960s most states passe

                                                      

2 On similarities and differences between genetic and non-genetic test

Michael J. Green and Jeffrey R. Botkin, “‘Genetic Exceptionalism’ in M

Clarifying the Differences between Genetic and Nongenetic Tests,” A

Internal Medicine 138 (2003): 571-575. 

3 A few states also screen newborns for infectious diseases: Massachus

New Hampshire screen infants for toxoplasmosis. Connecticut, Illinois, a

York screen for HIV; Connecticut and Illinois do so only if the mother 

tested for HIV during pregnancy. See the National Newborn Screening 

netic Resources Center’s “National Newborn Screening Status R

(November 10, 2008, version), available online at http://genes-r-us.uthscsa.ed

disorders.pdf. 

4 For example, couples of Eastern European Jewish descent who are con

ing marriage and childbearing may prospectively undergo carrier screen

Tay-Sachs disease, an invariably fatal genetic disorder that will affect 

quarter of their children if both parents are carriers of the defective gene. 
py

detected in that blood spot were added to the state screenin

grams: galactosemia (GALT), maple syrup urine disease (M

and homocystinuria (HCY) in the late 1960s, congenital hy

roidism (CH) in the 1970s, and sickle cell disease (SCD) 

1980s. Over the years, newborn screening has steadily expan

that today, depending on the state, an infant born in the 

States is likely to be screened for somewhere between twen

and fifty-four conditions. 

The practice of newborn screening varies from state to state

is no unified systematic approach at the national level. Ho

since 1985, the Council of Regional Networks for Genetic S

(CORN) has endeavored to provide public health services w

overall framework for a systems approach to newborn scre

Ideally, an effective newborn screening program includes t

lowing elements: education, screening, follow-up and dia

treatment, and evaluation. 

A. Education 

An effective newborn screening program must ensure that m

professionals, parents, and the general public are adequat

formed about newborn screening and the heritable disorders 

targets. Educating parents about newborn screening is a ch

that will only grow with the increasing number and comple

                                                      

5 See Bradford L. Therrell, et al., “U.S. Newborn Screening System Gu

Statement of the Council of Regional Networks for Genetic Services (C

Screening 1 (1992): 135-147; Kenneth A. Pass, et al., “US Newborn Screen

tem Guidelines II: Follow-Up of Children, Diagnosis, Manageme

Evaluation. Statement of the Council of Regional Networks for Genetic 

(CORN),” Journal of Pediatrics 137 (2000): S1-S46; and American Academ

diatrics, “Serving the Family From Birth to the Medical Home. N

Screening: A Blueprint for the Future,” Pediatrics 106 (2000): 389-422. 
ppg 

what will happen at the hospital when their baby is born.7 

studies have shown, most parents are only vaguely aware tha

newborns are being screened, even after the drawing of bloo

are even less aware of the particular conditions for which scr

is carried out: 

Very rarely did parents say they sought or received info

mation about newborn screening before their infant w

born. Many recalled receiving a newborn screening br

chure in a packet of information given to them during t

hospital stay after delivery; very few, however, report

reading it or remembering the information in the br

chure. Even fewer actually recalled being told anythin

about newborn screening while in the hospital. If th

were told anything, it was that their infant had a “bloo

test.” “The hospital visit was a fog; the only thing I want

to know was ‘is the baby OK?’”8

B. Screening 

The fact that parents of newborns are generally ignorant 

newborn screening is hardly surprising. The birth of a chi

momentous and exhausting experience for parents; so much 

                                                      

6 See Bradford L. Therrell, et al., “Status of Newborn Screening Program

United States,” Pediatrics 117 (2006): S212-S252, Table 3, “Responses to S

Processes Related to State/Territorial Newborn Screening Informatio

chures,” pp. S218-S219; and Kathryn E. Fant, et al., “Completen

Complexity of Information Available to Parents from Newborn-Screen

grams,” Pediatrics 115 (2005): 1268-1272. 

7 See Ellen W. Clayton, “Talking With Parents Before Newborn Screenin

nal of Pediatrics 147 (2005): S26-S29. 

8 Terry C. Davis, et al., “Recommendations for Effective Newborn S

Communication: Results of Focus Groups With Parents, Providers, a

perts,” Pediatrics 117 (2006): S326-S334. 
y

and breathing. The baby is also being measured, washed, and 

eye drops to prevent infection, a vaccine against hepatitis B

vitamin K shot to improve clotting. Sometime before the 

leaves the hospital (usually between twenty-four and nin

hours after birth), the heel is pricked and a few droplets of 

are squeezed out and absorbed onto a piece of filter paper, an

is the last that most parents will hear about genetic screen

their infant, unless a positive result is reported for one of 

says.9

 

The specimen of the baby’s blood is sent to a laboratory, 

concentrations of specific chemical compounds are measur

compared with the normal ranges expected for healthy 

Within the last five years, most screening laboratories in the 

States have begun to use a technology called tandem mass 

trometry (MS/MS) as the principal tool for analyzing ne

blood samples. MS/MS has made the screening process eas

cause it is a “multiplex testing platform,” i.e., it can be u

screen at once for over forty of the “inborn errors of metab

that comprise a large majority of the conditions targeted by 

born screening. These metabolic disorders detected by MS/M

be separated into three categories: fatty acid disorders, amin

disorders, and organic acid disorders. 

Fatty acid disorders are caused by deficiencies in the enzym

help the body derive energy from fat. Fat must be used as a 

of energy when the body runs out of glucose, the principal 

of energy production. If blood glucose levels are depleted a

                                                      

9 Some states require that infants be screened a second time, some days o

after birth, though most states require repeat screening only if the initial s

was performed less than twenty-four hours after birth. The purpose of 

peat screening is to catch disorders that for a variety of reasons might n

up in blood samples taken so soon after birth. 
ppp

acid disorders are medium-chain acyl-CoA dehydrogenase 

ciency (MCAD) and very long-chain acyl-CoA dehydro

deficiency (VLCAD). 

Amino acid disorders are caused by one of two sorts of enzy

ficiencies: either a failure of the enzymes needed to break 

certain amino acids, or a failure of the enzymes needed to 

body of ammonia (a by-product of amino acid metabolism) 

of the urea cycle. The buildup of amino acids or ammonia 

blood can cause severe medical complications, including men

tardation, developmental delays, failure to thrive, and death

examples of amino acid disorders are PKU and MSUD. 

Organic acid disorders involve deficiencies in the enzyme

normally help in the breakdown of amino acids (as well as, in 

cases, lipids and sugars). When these substances are not b

down, toxins accumulate in the body. The enzyme deficienc

farther down the pathways of amino acid metabolism, so t

not a buildup of amino acids but of certain organic acid inte

ates. Infants with these disorders are usually well at birth, b

soon develop poor feeding, irritability, lethargy, vomiting, and 

symptoms, including coma or death. Some of these disorder

later onset or milder symptoms. Two examples of organic ac

orders are isovaleric acidemia (IVA) and glutaric acidemia 

(GA1).10 

Before MS/MS was introduced for newborn screening, a se

assay was needed for each condition. Now only endocrine dis

                                                      

10 See the National Newborn Screening and Genetics Resource C

http://genes-r-us.uthscsa.edu/ for more information on these conditions
py 

are present in the sample and in exactly what concentratio

MS/MS, the two mass spectrometers are connected togethe

chamber called a collision cell. The collision cell’s job is to br

the molecules after one of the mass spectrometers has weigh

sorted them. The other mass spectrometer then sorts and 

the pieces of the molecules that are of interest to those cond

the screening. 

In newborn screening, the molecules whose concentratio

measured by MS/MS include amino acids (abnormal levels of 

indicate an amino acid disorder) and acylcarnitines (abnorma

of which indicate a fatty acid or organic acid disorder). T

mass spectrometry is the most reliable, widely available meth

measuring these compounds in a child’s blood.12 

Recent studies have shown that MS/MS also can be used to 

a class of genetic conditions known as lysosomal storage dis

including the rare Fabry, Gaucher, Krabbe, Niemann-Pic

Pompe diseases. Because clearly efficacious treatments are n

available for the lysosomal storage disorders, assays for these 

tions have not been included in most MS/MS newborn scr

                                                      

11 The hemoglobinopathies are detected by one of two other multiplex 

platforms: either high pressure liquid chromatography (HPLC) or isoele

cusing (IEF). Besides CH and congenital adrenal hyperplasia (CA

disorders that require separate assay platforms (“singletons”) include co

hearing loss, biotinidase deficiency (BIOT), cystic fibrosis (CF), and GAL

12 American College of Medical Genetics/American Society of Human G

Test and Technology Transfer Committee Working Group, “Tandem Ma

trometry in Newborn Screening,” Genetics in Medicine 2 (2000): 267-269

Banta-Wright and Robert Steiner, “Tandem Mass Spectrometry in N

Screening, A Primer of Neonatal and Perinatal Nurses,” Journal of Perin

Neonatal Nursing 1 (2004): 41-58; and Donald Chace, “A Layperson’s G

Tandem Mass Spectrometry and Newborn Screening,” onl

www.savebabies.org. 
g pp

care physician or pediatrician, who communicates them to th

ents. How the results of newborn screening are reported 

from state to state. Most states report abnormal results to th

hospital by letter, fax, phone call, or lab report. Normal resu

also usually reported to the birth hospital, though sometimes 

the pediatrician or the parents.14 Most of the time, abnormal 

are reported within a week after the screening. 

It is, however, important to recognize that an initial positive s

result is not the same as a diagnosis of disease. If for any reason th

ability of the initial screening result is questionable, a repe

may be ordered. Even if the screening result is considered r

the possibility of false positives means that more detailed con

tory testing (sometimes involving DNA analysis or 

quantitative methods) will be required before a definitive dia

is reached. With rare exceptions, when treatment for a detect

order is available, it is not started until after the diagn

confirmed. In the meantime, the parents will receive cou

about the possible implications of the positive result, wh

newborn is referred to the appropriate health care provid

proper medical evaluation, confirmatory testing, diagnosi

treatment. 

                                                      

13 See Michael Gelb, et al., “Direct Multiplex Assay of Enzymes in Drie

Spots by Tandem Mass Spectrometry for the Newborn Screening of Ly

Storage Disorders,” Journal of Inheritable Metabolic Disease 29 (2006): 397-40

Li, et al., “Direct Multiplex Assay of Lysosomal Enzymes in Dried Bloo

for Newborn Screening,” Clinical Chemistry 50 (2004): 1785-1796; and Da

lington, “Newborn Screening for Lysosomal Storage Disorders,” Clinical C

51 (2008): 808-809. 

14 See Franklin Desposito, et al., “Survey of Pediatrician Practices in Re

Statewide Authorized Newborn Screening Results,” Pediatrics 108 (200

and Kenneth D. Mandl, et al., “Newborn Screening Program Practice

United States: Notification, Research, and Consent,” Pediatrics 109 (200

273. 
jgp

threshold level too high, and a certain number of infants wh

ally have the disorder will go undetected; these are calle

negatives. Set the level too low, and most or all infants with t

order will be detected, but many additional infants will test p

without actually having the disorder. The rate of such false po

has been considerably reduced with the introduction of M

and other precise testing platforms. Such screening protoc

extremely sensitive (i.e., they successfully identify the vast m

of infants actually suffering the disorder) while being at the 

time extremely specific (i.e., the vast majority of positive resu

true positives, not false positives). Unfortunately when a pop

is screened for extremely rare disorders, even a highly speci

sensitive assay can yield very large numbers of false positives.

                                                      

15 To understand the problem of false positives, one has to consider not 

sensitivity and specificity of a screening protocol but also its positive pr

value, which is defined as the proportion of patients with positive test resu

are correctly diagnosed. Even if sensitivity and specificity are high, posit

dictive value can be quite low when the disease is very rare (i.e., w

prevalence of the disease is very low.) If PPV = positive predictive valu

sensitivity, Sp = specificity, and P = prevalence, it can be shown that 

⎟

⎠

⎞ ⎜

⎝

⎛

⋅ − − +

= ⋅ + − −

⋅ =

1 (1 ) 1 1

1

(1 )(1 )

Se P

Se P Sp P Sp

Se P PPV

Even more simply, if TP = true positives and FP = false positive

PPV = TP

TP + FP

, it follows that the ratio of false positives to true positive

FP

TP = (1 − Sp)Se ⋅ 1

P − 1 ⎛

⎝ ⎜ ⎞

⎠

⎟ 

These formulae mean that, no matter how high the test specificity (as lon

not 100 percent), a sufficiently rare disease (i.e., low prevalence P) can m

positive predictive value of a test extremely low and the ratio of false 

results to true positive results correspondingly high. 
y gg 

The other 1,231 out of 1,249 positive results turned out 

false.17 Pediatrician Beth Tarini and colleagues have calculate

the screening of all American newborns for metabolic disord

MS/MS is likely to yield some tens of thousands of false p

results per year.18

Such high rates of false positives may be an unfortunate b

avoidable side effect of trying to identify every infant with 

genetic disorder. Concerns have been raised, however, abo

potential impact of false positive screening results on parenta

ety and stress, parent-child relationships, and perceptions 

child’s health,19 and there is always the risk that a child inco

identified as suffering from a genetic disorder will be given 

propriate treatment before further testing establishes that the 

screening result was false. In Chapter Three, we shall return 

                                                      

16 Data downloaded from the National Newborn Screening Information 

available online at www2.uthscsa.edu/nnsis. 

17 With sixty-eight false positives for every true positive detected, and 

mated prevalence of one in 180,000, newborn screening for MSUD in 20

positive predictive value of about 1.4 percent, which would be consisten

sensitivity approaching 100 percent and a specificity as high as 99.96 

This shows vividly how an extraordinarily sensitive and specific test can n

less yield high numbers of false positives if the targeted condition is exc

rare. See Andreas Schulze, et al., “Expanded Newborn Screening for Inb

rors of Metabolism by Electrospray Ionization-Tandem Mass Spectr

Results, Outcome, and Implications,” Pediatrics 111 (2003): 1399-1406. 

18 Beth Tarini, et al., “State Newborn Screening in the Tandem Mass Spe

try Era: More Tests, More False-Positive Results,” Pediatrics 118 (2006): 4

They calculated a best-case scenario of 2,575 false positives per year, and 

case scenario of 51,059 false positives per year, but this was for the ye

before most states had implemented the ACMG’s expanded screening pan

19 See, for example, Elizabeth Gurian, et al., “Expanded Newborn Scree

Biochemical Disorders: The Effect of a False-Positive Result,” Pediatrics 6 

1915-1921. The psychosocial impact of false positive screening results 

explored further in Chapter Three. 
g pp

positive result. 

D. Treatment and Evaluation 

Newborns confirmed to have a genetic disease need to be r

to metabolic specialists, endocrinologists, hematologists, o

monologists who will be responsible for developing a specif

for the care and treatment of the child. In many cases, diseas

agement will continue throughout the affected child’s life. Fo

serious genetic diseases, the treatment is simple, inexpensive

tive, and relatively unobtrusive. Thus, for the one in 4,000 c

suffering from congenital hypothyroidism, a daily thyroxin 

makes possible a normal life instead of a grim future of grow

ure and permanent mental retardation. For other disorde

treatment is difficult but manageable. Thus children diagnose

PKU can grow up free of its devastating neurological sympto

maintaining a diet low in phenylalanine for the rest of thei

This course of treatment is effective but quite burdensome

entails severely restricting (or eliminating) the eating of 

phenylalanine foods such as breast milk, meat, chicken, fish

cheese, and legumes. 

For certain other detectable genetic disorders, as we shall s

prognosis is much less clear, and the appropriate course of 

ment is not known with certainty. Moreover, even when a tre

is “available,” many other steps have to be taken to reali

treatment’s benefits for the affected children. Not only mu

diagnosis be confirmed, but resources must be effectively an

sistently delivered to the child and family over a long per

time. In some cases, state newborn screening programs ma

quately fund the detection of genetic disorders without ensurin
y

chiefly among African-American infants; but a 2003 study re

that children affected with SCD received, on average, only 

percent of the recommended medication (i.e., the mean num

days of the year that an affected child received the antibiot

only 148).21 Clearly, success at identifying infants with the 

does not guarantee that children are truly benefiting from ne

screening for SCD; yet SCD screening is a well-established pr

and is widely considered one of the more successful examp

mandatory newborn screening.22

Finally, to establish that a certain newborn screening prog

truly effective, rigorous evidence-based studies are needed t

out whether early detection and intervention produce a trul

tive outcome for the affected infants. Yet, all too often, disea

added to mandatory screening panels without adequate pilot 

establishing the efficacy of detection and intervention, an

without adequate follow-up studies evaluating all the lon

consequences, both good and bad, for the children identified 

program. In 1992, Norman Fost examined the unintended 

                                                      

20 See Celia I. Kaye, et al., “Assuring Clinical Genetic Services for Ne

Identified Through U.S. Newborn Screening Programs,” Genetics in M

(2007): 518-527. 

21 Colin M. Sox, et al., “Provision of Pneumococcal Prophylaxis for Pub

sured Children with Sickle Cell Disease,” Journal of the American Medical A

290 (2003): 1057-1061. As for why the children do not receive proper med

Sox and his colleagues wrote the following: “Reasons for such poor prov

prophylactic medication are unknown, but may include physicians not 

prescriptions for prophylactic antibiotics or patients not taking written p

tions to the pharmacy. Notably, children frequently interacted with th

care system, with a mean of 13 outpatient encounters per year, suggestin

missed opportunities to emphasize and assess compliance with proph

(Ibid., p. 1060.) 

22 Richard S. Olney, “Preventing Morbidity and Mortality from Sickle C

ease: A Public Health Perspective,” American Journal of Preventive Medicine 16 

116-121. 
p

by well-designed empirical studies.23 In Chapter Two of this 

paper, we return to this question of the efficacy of newborn s

ing as we examine the expansion in state-mandated ne

screening programs that is occurring today. 

II. Public Policy and Newborn Screening 

Both federal and state governments make policy governing 

born screening, but the federal government has so far pl

comparatively limited role in shaping screening programs. It 

grants to help states pay for screening costs and research.24 

working committees designed to explore the ethical, social, c

and political implications of newborn screening.25 It ensur

laboratories processing the screening tests meet strict standar

                                                      

23 Norman Fost, “Ethical Implications of Screening Asymptomatic Indiv

FASEB (Federation of American Societies for Experimental Biology) Journal 6 

2813-2817, p. 2814. 

24 Section 300b-8 of Title 42 of the United States Code states that the Sec

the Department of Health and Human Services (HHS) must award grants 

ties to improve state and local health agencies’ ability to provide sc

counseling, or health care services to newborns and children who have o

risk for heritable disorders. See also Sections 300b-1, 300b-6, and 300

more details on the federal government’s role. 

25 Section 300b-10 of Title 42 states that the Secretary must establish the 

sory Committee on Heritable Disorders in Newborns and Children

Committee is to offer advice to the Secretary on grants awarded under Se

8. 

26 The Clinical Laboratory Improvement Amendments of 1988 (CLIA-88

improved upon the Clinical Laboratory Improvement Act of 1967 (CLIA

the law that permits the Secretary of HHS to create quality standards for 

tory testing. Laboratories can choose to receive CLIA certification eithe

appropriate state agency or by an approved private organization, such as t

Commission on Accreditation of Healthcare Organizations, the Co

American Pathologists, or the American Society for Histocompatibility 

munogenetics. HHS, through the Centers for Medicare and Medicaid 

published most of the regulations pertaining to CLIA in 1992. 
jp

tions for which newborns will be screened. Each state is respo

                                                                                                          

 At the time CLIA-88 was enacted and its regulations formulated, 

was just becoming available and the Human Genome Project was just be

Much in genetics and genetic testing has changed since then. So while 

testing laboratories are still subject to CLIA-88, some have argued that 

offers very little guidance regarding genetic testing. As far back as 1997, 

tional Institutes of Health-Department of Energy Task Force on Genetic 

issued a report (Promoting Safe and Effective Genetic Testing in the United States

for the HHS Clinical Laboratory Improvement Advisory Committee (CL

recommend the creation of a subspecialty on genetics in order to add

shortcoming of CLIA-88. CLIAC then proposed some changes to the re

in 1998. In 2000, the Secretary’s Advisory Committee on Genetic 

(SACGT), the predecessor to the Secretary’s Advisory Committee of G

Health, and Society (SACGHS), also acknowledged this shortcoming of 

and supported CLIAC’s recommendations. In 2003, HHS revised the CLI

lations and included some of CLIAC’s proposals. Nevertheless, some co

to maintain that a separate subspecialty for genetic screening should be 

But in November 2006, CMS told SACGHS that there is no need for a 

cialty for genetic testing, and that in fact CLIA-88 regulations already ful

genetic testing. For more information see the CMS website, www.cms.hhs

 In addition to the role of CMS, the Centers for Disease Control and 

tion’s Environmental Health Laboratory evaluates the performa

laboratories involved in the analysis of newborn screening tests and p

technical assistance to resolve diagnostic problems. For more information 

CDC website, www.cdc.gov. 

27 The Food and Drug Administration (FDA) is responsible for ensu

safety and efficacy of medical devices. Included within this category are 

test kits, including newborn screening test kits. Recently, the FDA has be

sidering the safety and efficacy of MS/MS. In fact, in 2004 the Ce

Devices and Radiological Health of the FDA published detailed guida

industry and FDA staff on the use of MS/MS. See the following for mo

mation: Center for Devices and Radiological Health, Food and 

Administration, “Class II Special Controls Guidance Document: N

Screening Test Systems for Amino Acids, Free Carnitine, and Acylcarnit

ing Tandem Mass Spectrometry,” November 24, 2004. For more informa

the FDA website, www.fda.gov. 

28 The Federal Trade Commission (FTC) regulates these aspects of the t

the FTC website, www.ftc.gov, for more information. 
gy 

how to organize and conduct their own screening programs

states have at least a few similar policies. For example, many 

have privacy and confidentiality policies to protect personal 

mation, including genetic information. Many states allo

parents to opt out of the screening. And many states have 

tion programs that provide parents with information o

screening process, such as the conditions being screened for

scription of the conditions, the manner of the collection proc

and an explanation of why the health care professionals migh

to retest.30

Just as there are important similarities among the programs

are also some differences. One of the main differences is 

quality of parental education. Many states do not provide p

with information on the accuracy of screening, the possib

false positives, when the results of the screening tests will be 

able, the privacy and confidentiality laws governing the infor

obtained, or how the parents might decline the offer for scre

The states also differ in the fees charged for newborn scre

Some states charge no fee at all, while other states charge as 

as $140.31 Still another difference is in the number of initial s

ing tests required, with some states requiring only one test 

conducted and other states requiring two initial tests.32 

                                                      

29 See Kay Johnson, et al., “Financing State Newborn Screening Pr

Sources and Uses of Funds,” Pediatrics 117 (2006): S270-S279; and Brad

Therrell, et al., “Status of Newborn Screening Programs,” S212-S252. 

30 Ibid. 

31 Where no fee is charged, the cost of screening is covered by a combin

state and federal revenues. If a fee is charged, it may be paid by Medicaid, 

private insurers, health providers, laboratories, hospitals, or the parent

selves. (Kay Johnson, et al., “Financing State Newborn Screening Pr

Sources and Uses of Funds,” pp. S271, S276.) 

32 Bradford L. Therrell, et al., “Status of Newborn Screening Programs.” 
y g 

conditions, and some states screen for as many as fifty-s

Many of these conditions were added to state screening pa

the past few years, in response to recommendations issued i

by the American College of Medical Genetics (ACMG). In th

chapter we turn to a detailed analysis of the ACMG’s ne

screening recommendations and the ethical issues they raise. 

\[

                                                      

33 See the National Newborn Screening and Genetics Resource Cente

tional Newborn Screening Status Report” at http://genes-r-us.uthscsa.edu

nbsdisorders.pdf. 
21

THE CHANGING PRINCIPLES 

AND PRACTICE OF NEWBORN 

SCREENING 

e now turn to the ethical principles that have 

newborn screening in this country since the 1960s

ciples that are today being challenged as the 

rapidly expand their newborn screening programs. A new reg

expanded newborn screening is being implemented in most 

in large measure as a response to recommendations advan

the ACMG in a report published in 2005. That report has s

controversy, with some critics arguing that the expansion o

born screening is proceeding too rapidly and without suf

deliberation and care. We explore these developments in th

sent chapter, first by introducing and explaining the c

principles of newborn screening, and then by assessin

ACMG’s recommended expansion and the controversy it ha

voked. We are especially interested in the following question

expansion recommended by the ACMG consistent with the 

cal ethical principles of screening, or does it represent a 

departure? 

I. The Classical Principle: Screen Only If You Can 

 Effectively Treat 

From the late 1960s until recently, there was a durable consen

the ethical principles that ought to guide the practice of ne

screening. The most in-depth and influential presentation of 

principles was the 1968 World Health Organization monogr

James Wilson and Gunnar Jungner, Principles and Practice of S

W
pp

ognized disease. 

3. Facilities for diagnosis and treatment should be available. 

4. There should be a recognizable latent or early sympt

stage. 

5. There should be a suitable test or examination. 

6. The test should be acceptable to the population. 

7. The natural history of the condition, including develo

from latent to declared disease, should be adequately 

stood. 

8. There should be an agreed policy on whom to treat as pa

9. The cost of case-finding2 (including diagnosis and treatm

patients diagnosed) should be economically balanced in r

to possible expenditure on medical care as a whole. 

10. Case-finding should be a continuing process and not a 

and for all” project.3

                                                      

1 James M. G. Wilson and Gunnar Jungner, Principles and Practice of Scr

Disease (Geneva: World Health Organization, 1968), available online at 

doc.who.int/php/WHO_PHP_34.pdf. 

2 By case-finding, Wilson and Jungner mean “that form of screening of w

main object is to detect disease and bring patients to treatment, in con

epidemiological surveys.” In contrast, the main purpose of surveys is 

bring patients to treatment but to elucidate the prevalence, incidence, and 

history” of the disease or symptom under study. (Ibid., p. 12.) 

3 Ibid., pp. 26-27. 
In adhering to the principle of avoiding harm to the p

tient at all costs (the primum non nocere of Hippocrate

treatment must be the first aim. For declared disease the

is, of course, the ethical obligation to provide an accept

treatment whether or not this is of scientifically prov

value; but, when new territory is being explored by the early det

tion of disease, it is clearly vital to determine by experimental surv

whether a better prognosis is given by treating the conditions found 

an earlier stage than was previously the practice. Unless this is s

there can be no advantage to the patient and, in fact, 

alerting him or her to a condition that has not been shown to bene

by treatment at an earlier stage actual harm may be done.

5

The third Wilson-Jungner criterion—the availability of facilit

diagnosis and treatment—means that a large-scale screenin

gram cannot be justified unless resources will be available b

confirm the diagnosis and to treat effectively those who are 

fied as having the disease. As we shall see, this can be an is

state-mandated newborn screening if states have the resou

screen newborns for a condition but not necessarily to fol

and manage the care of all those who test positive. 

The seventh Wilson-Jungner criterion—that there must be an a

understanding of the natural history of the disease—is also highly pe

to the subject of this white paper. Wilson and Jungner sugge

tain questions that need to be answered about a medical con

before screening can be justified: 

 What changes should be regarded as pathological an

what should be considered physiological variations? 

                                                      

4 Ibid., p. 27; emphasis added. 

5 Ibid., pp. 27-28; emphasis added. 
g 

and before controlled clinical trials have established the eff

ness and benefits of intervention: 

Without well-planned surveys, carried out in advance 

the main body of medical opinion, the view that early d

agnosis and treatment successfully improves the outloo

for the condition in question is likely to become genera

accepted. This in turn automatically renders unethic

planned randomized trials of intervention by treatmen

following early diagnosis; with the result that ideas abo

the effect of treatment pass into the realm of folklo

rather than of scientific knowledge.7

Although not specifically formulated for pediatric screenin

Wilson-Jungner criteria have largely guided the practice of ne

screening over the past four decades. Thus, in an importan

paper on the principles that should govern pediatric screenin

diatrician William K. Frankenburg presented those principl

way that clearly echoed the work of Wilson and Jungner: 

The availability of a suitable screening test does not justi

screening for a disease unless the disease is importan

relatively prevalent, and amenable to early treatmen

Screening for a disease which has the necessary characte

istics cannot be justified unless there is an acceptab

reliable and valid test which can be carried out at reaso

able cost. 

                                                      

6 Ibid., p. 32. 

7 Ibid., p. 28. 

8 William K. Frankenburg, “Selection of Diseases and Tests in Pediatric 

ing,” Pediatrics 54 (1974): 612-616. 
yp

the four U.S. National Academies) on assessing genetic ris

ommended that “newborn screening only take place 

conditions for which there are indications of clear benefit 

newborn, 2) when a system is in place for confirmatory dia

and 3) when treatment and follow-up are available for a

newborns.”10 In 1995, the American Society of Human G

(ASHG) and the ACMG issued a joint report affirming that “

medical benefit to the child should be the primary justificati

genetic testing in children and adolescents,”11 and this judgme

reaffirmed by a 1997 report by the NIH Task Force on G

Testing.12 In 2000, a report by the American Academy of Ped

stated that a condition is a good candidate for newborn scr

only if “the treatment for the condition is effective when in

early, accepted among health care professionals, and availabl

screened newborns.”13 In all these statements of principle, dir

fit to the newborn child was identified as the paramoun

indispensable criterion for inclusion of a disease in a u

screening panel. To justify such inclusion, the natural history 

disease must be well understood, the diagnostic test for its pr

                                                      

9 Ibid., p. 616. 

10 Committee on Assessing Genetic Risks, Institute of Medicine, Assessin

Risks: Implications for Health and Social Policy, Lori B. Andrews, Jane E. F

Neil A. Holtzman, and Arno G. Motulsky, eds. (Washington, D.C.: N

Academies Press, 1994).

11 American Society of Human Genetics and American College of Med

netics, “Points to Consider: Ethical, Legal, and Psychosocial Implica

Genetic Testing in Children and Adolescents,” American Journal of Human 

57 (1995): 1233-1241, p. 1233. 

12 Neil A. Holtzman and Michael S. Watson, Promoting Safe and Effectiv

Testing in the United States: Final Report of the Task Force on Genetic Testing (B

Maryland: National Institutes of Health, 1997), available online at http://b

law.lsu.edu/research/fed/tfgt/. 

13 American Academy of Pediatrics Newborn Screening Task Force, “Ser

Family from Birth to the Medical Home. Newborn Screening: A Blueprin

Future,” p. 394. 
four National Academies) began by stating that newborn scr

is appropriate when there is evidence that it provides “subs

public benefit,” i.e., benefit not limited to the timely and ef

treatment of the infant’s condition. The report went on to d

three forms of such benefit other than direct treatment: 1) 

infant (to provide management and support even when 

treatment is unavailable), 2) to the family (to inform subs

reproductive decisions), and 3) to society (to provide knowle

the true range and incidence of the condition).14

Meanwhile, in recent years some prominent figures in the w

newborn screening—including the director of the National In

of Child Health and Human Development (NICHD)—have 

fully criticized the principle that “it is appropriate to screen o

conditions for which effective treatment already exists” 

“dogma” that ought to be discarded. They favor a signif

more expansive approach to newborn screening, in which all 

tions—no matter how rare, poorly understood, or cu

untreatable—are presumed to be eligible for screening unle

cifically excluded on a case-by-case basis.15 At the same tim

NICHD is funding efforts to move beyond today’s limited, p

typic methods of newborn screening toward DNA-based pla

that can “offer enormous opportunities to identify staggering 

bers of potentially pathogenic mutations in a very large num

disease-associated genes.”16 Clearly, proponents of this chan

                                                      

14 National Research Council Committee for the Study of Inborn Errors 

tabolism, Genetic Screening Programs, Principles, and Research (Washington

National Academy of Sciences, 1975), p. 1. 

15 Duane Alexander and Peter C. van Dyck, “A Vision of the Future of N

Screening,” Pediatrics 117 Supplement (2006): S350-S354. 

16 Duane Alexander and James W. Hanson, “NICHD Research Initiative 

born Screening,” Mental Retardation and Developmental Disabilities Research R

(2006): 301-304, p. 302. 
g pg 

not to screen.” 

II. Newborn Screening and the ACMG’s Expanded Un

 Panel 

This scenario is no longer entirely hypothetical; change has 

come to the practice of newborn screening in this country. 

past few years, newborn screening has undergone rapid exp

throughout the United States in accordance with recommend

made by the ACMG in its 2005 report, Newborn Screening: To

Uniform Screening Panel and System.

17 That document is the final 

of an ACMG working group commissioned and funded in 2

the federal Maternal and Child Health Bureau (MCHB) 

Health Resources and Services Administration, a division of 

The ACMG’s task was to gather evidence on the effectiven

newborn screening, to recommend a uniform panel of con

that ought to be screened for in every state, and to conside

critical components of the newborn screening system.18 In 

port, the ACMG recommended that all state-based ne

screening programs adopt a uniform panel of twenty-nine co

ditions as well as twenty-five secondary conditions.19 

recommendation was promptly endorsed by the Advisory Co

                                                      

17 American College of Medical Genetics, Newborn Screening: Toward a 

Screening Panel and System (Washington, D.C.: Health Resources and Serv

ministration, 2005), hereafter cited as ACMG, Newborn Screening. The full 

available online at http://mchb.hrsa.gov/screening (the version cited h

(in a version published as a supplement to Genetics in Medicine 8 [2006]: 

252S) at www.acmg.net/resources/policies/NBS/NBS-sections.htm. 

18 ACMG, Newborn Screening, p. 7. 

19 The crucial distinction between core and secondary conditions is e

later in the chapter. For the present, let the primary or core conditions b

stood as those that fully meet the criteria for inclusion in the uniform s

panel, while the secondary conditions are those that fall short of that s

but—according to the ACMG—merit inclusion in the panel on other gro
unprecedented speed to implement a newborn screening 

that is both considerably more uniform and considerably exp

compared to even a few years ago. For comparison, as rece

2005 (the year the ACMG report was released), the states 

widely in their use of newborn screening tests, “with some m

ing screening for as few as three conditions and others man

as many as forty-three conditions.”23 

                                                      

20 In its letter, the Advisory Committee “strongly and unanimously recom

that the Secretary initiate appropriate action to facilitate adoption of the 

recommended screening panel by every State newborn screening program

letter may be found online at www.hrsa.gov/heritabledisorderscommittee

reports/letterstoSecretaryofHHS.htm. 

21 More precisely, as of November 2008, all of the states screen for 

twenty-six of the twenty-nine core conditions, and forty-four states scree

of them. See the screening statistics compiled by the National Newborn 

ing and Genetics Resource Center (NNSGRC) at http://genes-r-us.uthscs

nbsdisorders.pdf. Note that the NNSGRC status report may not accur

flect the mandatory or voluntary status of newborn screening in each st

example, Massachusetts currently offers two screening panels, a mandato

of ten conditions and an optional panel of twenty others. 

22 More precisely, as of November 2008, thirty states are now or soon 

screening for more than twenty of the twenty-five secondary condition

other end of the spectrum, three states (Arkansas, Kansas, and Louisiana

for only two of the secondary conditions. 

23 ACMG, Newborn Screening, p. 7. According to a November 2008 repor

CDC, “After 2006, most states began to expand their panels to includ

disorders; currently, 21 states and the District of Columbia have fully 

mented the ACMG panel.” The CDC also analyzed newborn screening da

2001 to 2006 from states with well-established MS/MS screening prog

“estimate the number of children in the United States who would ha

identified with disorders in 2006 if all 50 states and the District of Colum

been using the ACMG panel.” This analysis led the CDC to conclude th

an expansion would have increased the number of children identified in 

only thirty-two percent (from 4,370 to 6,439). But the additional children 

fied would have had “many rare disorders that require local or regional 

to deliver expertise in screening, diagnosis, and management.” Accordin

CDC's analysis, nine of the disorders detectable by MS/MS each accou
ppgg p

years? Or has there been a break with those principles, and

how significant a break? Answering these questions requires 

look at some features of the ACMG’s complex and lengthy re

In carrying out its mandate, the ACMG working group eva

eighty-four heritable disorders for possible inclusion in a u

newborn screening program that all fifty states would be e

aged to adopt. After conducting a broad survey of expert o

the working group assigned a numerical score to each con

with a high score indicating that the condition was a plausib

didate for mandatory screening. The eighty-four condition

initially divided into three groups, composed of high-, middl

low-scoring conditions. In a second tier of analysis, each cond

initial ranking was re-evaluated by a small number of expert

which the conditions were assigned to one of three final cate

a core panel of conditions meriting mandatory screening (t

nine conditions); a secondary panel of conditions not meeti

standards of the core panel but deemed appropriate for scr

anyway (twenty-five conditions); and the remaining cond

deemed not appropriate for screening at this time.25

                                                                                                          

an estimated fifteen cases or fewer; in contrast, SCD and CH (both alre

geted by population-wide screening in the United States) together accou

sixty-one percent of the total estimated number of cases. See Centers for 

Control and Prevention, “Impact of Expanded Newborn Screening—

States, 2006,” Journal of the American Medical Association 300 (2008): 2242-22

24 The report itself is 108 pages long, with an additional 221 pages of figu

appendices. 

25 ACMG, Newborn Screening, pp. 9-10. The working group deferred a 

regarding screening for three infectious diseases included among the eig

conditions evaluated: human HIV infection, congenital toxoplasmosis, a

genital cytomegalovirus infection. See p. 66. 
y 

of Pediatrics,26 by the March of Dimes,27 and by other ad

groups and professional organizations. At the same time, the 

ods by which the ACMG working group arrived 

recommended screening panels have been faulted on a num

grounds, leading some critics to conclude that the expans

newborn screening is proceeding too rapidly and without suf

deliberation and caution. Others have defended the propos

pansion against these criticisms. Before giving our own asse

of the ACMG’s report, let us briefly summarize the objectio

have been raised by others. 

Commenting on the ACMG’s recommendations, pediat

ethicist Jeffrey Botkin and colleagues urge a cautious appro

expansion.28 They note that, even in its most celebrated and 

digmatic successes (e.g., PKU), newborn screening has prove

a mixed blessing, with adverse consequences as well as be

That is, although they consider PKU screening to be a clear s

they point to avoidable missteps in its implementation and to 

continuing adverse consequences, largely from false positive s

ing results. They also caution that each genetic illness is uniqu

population-wide screening of asymptomatic individuals fo

common diseases has rarely proved effective; that the benef

risks must be carefully weighed on a condition-by-condition 

and that rapid expansion of the uniform screening panel w

adequate empirical studies would be unwise. 

                                                      

26 “AAP Endorses Newborn Screening Report from the American Co

Medical Genetics,” press release of May 12, 2005, available on

www.aap.org/advocacy/releases/mayscreening.htm. 

27 “March of Dimes Statement on Newborn Screening Report,” Septem

2004, available online at www.marchofdimes.com/aboutus/10651_13507

28 Jeffrey R. Botkin, et al., “Newborn Screening Technology: Proceed W

tion,” Pediatrics 117 (2006): 1793-1799. 
screening. The questions that would need study include: D

benefits of screening for this disorder outweigh the harms, 

What are the actual medical, psychological, and social outcom

infants testing positive for the disorder? How common are 

positive results, and what are their consequences? What are t

ondary benefits of screening to the family and to the public, a

they substantial enough to justify screening when the trad

standard of direct medical benefit to the child cannot be met

research would be conducted in carefully controlled pilot s

with the aim of gathering vital information about the risk

benefits involved, well before the implementation of popu

wide newborn screening.29 

Pediatrician Virginia Moyer and colleagues (including Jeffre

kin, among others), writing on behalf of the United 

Preventive Services Task Force (USPSTF), have criticize

ACMG working group for failing to “conform to contem

standards of evidence-based decision-making.”30 They co

that a “technological imperative”31 has driven the ACMG to i

in the recommended panel diseases that are poorly understoo

treatable, or both, merely because the technology exists to 

them. Believing that the goal of screening should be to impro

health of affected newborns, they find it ethically questiona

                                                      

29 Of course, for the rarer conditions, affecting fewer than one in 10,0

borns, it will prove quite difficult to conduct statistically valid research on 

subpopulations prior to full-scale screening. For a proposal for a struct

quence of research protocols to evaluate potential applications for n

screening before their formal implementation in public health programs, 

fey R. Botkin, “Research for Newborn Screening: Developing a N

Framework,” Pediatrics 116 (2005): 862-871. 

30 Virginia A. Moyer, et al., “Expanding Newborn Screening: Process, Po

Priorities,” Hastings Center Report 38 (2008): 32-39, p. 33. 

31 Ibid., p. 33. 
py g gp 

conditions for inclusion was flawed, insofar as it relied on 

tematic reviews and colloquial evidence and made use of dub

obscure criteria. Applying USPSTF decision-making stan

Moyers and colleagues find that for only a handful of the t

nine recommended conditions is there adequate evidence th

benefits of screening would outweigh the harms. They sugge

“state and federal policymakers should further evaluate each 

tion proposed for screening before recommending that 

included in a mandated screening panel.”34 Finally, Moyers an

leagues urge states that implement the expanded panels to “c

to collecting longitudinal data on infants who test positive

help us implement in the future truly effective evidence

screening programs. 

Mary Ann Baily and Thomas Murray of the Hastings Cente

offered a somewhat different critique of the ACMG’s r

mended expansion of newborn screening.36 They emphasize 

responsible newborn screening policy must take into accou

opportunity costs of expanded screening, which will inevitabl

scarce resources away from other worthy public health pro

and needs. They point out that the true costs of a newborn s

ing program include not only the price of the test itself 

might seem quite small) but also the cost of “parental edu

follow-up of all positives to a definitive diagnosis, treatment 

fected children, and ongoing data collection and evaluation

light of these concerns about allocation of health care reso

                                                      

32 Ibid., p. 34. 

33 Ibid., p. 35. 

34 Ibid., p. 33. 

35 Ibid., p. 39. 

36 Mary Ann Baily and Thomas H. Murray, “Ethics, Evidence, and Cost 

born Screening,” Hastings Center Report 38 (2008): 23-31. 

37 Ibid., p. 27. 
gpg y g

conditions will help families of affected infants to “avoid a di

tic odyssey,” they urge that these benefits be weighed again

burdens of different kinds of odysseys.” First, there is “the 

of anxious searching and wandering” that many families of h

children will experience between an initial false positive resu

the confirmatory testing that eventually reassures them tha

children are well. Second, there will be families whose childr

diagnosed with a serious genetic disorder and yet never b

symptomatic: 

Perhaps the child has a mild or subclinical form that w

unknown before newborns were routinely screened for t

disorder... Meanwhile, the family reorganizes its li

around medical monitoring and planning for somethin

terrible that never happens.39

 

Third, there will be children who are accurately diagnosed w

orders for which there are as yet no proven treatments. 

families may begin a “treatment odyssey, searching the In

visiting specialists, running up debt, medicalizing the child’s 

only to have that life end in early death anyway.”40 Baily and M

fear that, with expanded screening, such unhappy medical od

will become more widespread. 

Rebutting such criticisms, R. Rodney Howell, pediatricia

member of the ACMG’s Newborn Screening Steering Com

that supervised the preparation of the 2005 report, observe

controversy over the current expansion is reminiscent of ea

position to PKU screening when it was introduced over fort

                                                      

38 Ibid., p. 28. 

39 Ibid., p. 29. 

40 Ibid., p. 29. 
ggp

require a complex infrastructure (to support testing, coun

education, treatment, and follow-up) that is not yet in place. 

fended the efficacy of newborn screening in general, howev

pointed out that “there is little advantage at this time to 

whether there should be expansion of newborn screening; it 

curring briskly at this very moment.”42 Indeed, it is notab

both those urging caution and those enthusiastically embrac

expansion of newborn screening are more or less in agreeme

rapid expansion is already taking place, and even more acce

expansion in the future is all but inevitable. 

Howell acknowledged the lack of controlled trials for the tre

of some of the serious metabolic disorders included in the r

mended panel, but he insisted that, when the evidence is cle

untreated infants face grave illness or death and that treatme

some efficacy, “no prudent physician would fail to provide 

ment information to such families if the condition had 

identified.”43 Addressing the issue of false positives, How

knowledged that they are problematic and called for more re

to keep their numbers to a minimum. Regarding informed p

consent, Howell considered it desirable in the case of poorly 

stood conditions, but he noted that it is a daunting challenge 

to explain to parents the array of tests to be performed a

various potential outcomes of accepting or rejecting them. F

Howell predicted that, with new technologies and new treat

the number of genetic disorders for which newborns w

screened in the future will expand far beyond the currently r

mended panel, and he urged the nation to get to work build

                                                      

41 R. Rodney Howell, “We Need Expanded Newborn Screening,” Pedia

(2006): 1800-1805, p. 1802. 

42 Ibid., p. 1802. 

43 Ibid., p. 1802. 
the ACMG’s approach: their use of a broadened conception of be

justify newborn screening, and their readiness to allow prog

multiplex screening technology to dictate the pace and scope of t

pansion of newborn screening. Before turning to these issues

first examine the principles that guided the composition 

ACMG’s core and secondary screening panels. 

B. The Core or Primary Conditions 

On a first reading, the ACMG report conveys a strong imp

of having followed accepted screening principles in recomm

its expanded uniform panel. Consider the following clear sta

of a “basic principle developed at the onset of the project”: 

To be included as a primary target condition in a newbo

screening program, a condition should meet the followin

minimum criteria: 

 It can be identified at a period of time (24 to 48 

hours after birth) at which it would not ordinarily 

be clinically detected. 

 A test with appropriate sensitivity and specificity is 

available. 

 There are demonstrated benefits of early detection

timely intervention, and efficacious treatment.44

Elsewhere the report affirms that, when evaluating a disord

inclusion in the screening panel, “benefit to the child 

screened is the overriding consideration.”45 Ultimately, the t

                                                      

44 ACMG, Newborn Screening, p. 28. 

45 Ibid., p. 42. 
And indeed, a review of the twenty-nine conditions desi

“core” or “primary” reveals that, in every case, the ACMG w

group concluded that effective treatment was available that 

prevent all (for four conditions), most (ten), or, at any rate

(fifteen) of the disease’s symptoms; they also determined tha

was clear (fourteen) or some (fifteen) evidence that treatment 

benefit the affected newborn. Finally, for twenty-five of the t

nine core conditions, the ACMG concluded that the av

treatment was efficacious at preventing mortality, independ

any reduction in morbidity.47

Whether all twenty-nine of the core conditions do actually m

chief criterion—the availability of an effective treatment th

clearly benefit those newborns who test positive for the 

tion—is open to debate.48 In this context, it is significant 

comprehensive study of the effectiveness and cost-effectiven

newborn screening for metabolic disorders in the United Kin

concluded in 2004 that the evidence supports screening fo

two of the conditions detectable by MS/MS: PKU and MCA

for the other conditions identifiable by MS/MS, the author

cluded the following: 

                                                      

46 Ibid., p. 62. Note that these three benchmarks correspond roughly to t

seventh, and second Wilson-Jungner criteria, respectively. 

47 These numbers are collected in a helpful review of the ACMG report b

ald Bailey and colleagues; Donald B. Bailey, Jr., et al., “Changing Perspec

the Benefits of Newborn Screening,” Mental Retardation and Developmental 

ties Research Reviews 12 (2006): 270-279, p. 273, Table 1. 

48 In addition to the article by Moyer, et al., “Expanding Newborn Sc

Process, Policy, and Priorities,” see Marvin Natowicz, “Newborn Scre

Setting Evidence-Based Policy for Protection,” New England Journal of Med

(2005): 867-870. 
The British recommendation to screen only for two metabo

orders was based on a systematic analysis of the same eviden

led the ACMG working group, a year later, to include twenty 

tions detectable by MS/MS in its core panel of twenty-nin

twenty-two more in its secondary panel of twenty-five conditio

which we now turn our attention. 

C. The Secondary Conditions 

Besides the twenty-nine core or primary conditions, the ACM

port also recommended mandatory screening for twen

“secondary” conditions that did not meet the three criteria (li

the preceding section) for inclusion among the core cond

More precisely, these are conditions that, despite the availabil

specific and sensitive screening test, lacked a well understood 

ral history, an efficacious treatment, or both. Why, then, we

recommended for mandatory screening? 

When first introduced in the ACMG report, the secondary 

tions are described as “conditions that are part of the diffe

diagnosis of a core panel condition.”50 In other words, som

conditions, in order to be diagnosed with precision, requ

gathering of data that also would reveal the presence in th

born of one or more other conditions—conditions whose 

history is poorly understood or for which effective treatment 

currently available. The necessity of screening for these sec

conditions would therefore seem to be a mere accident of th

ing protocol, an unintended and even regrettable conseque

the determination to screen for the core conditions. The A

                                                      

49Abdullah Pandor, et al., “Clinical Effectiveness and Cost-Effectiveness 

natal Screening for Inborn Errors of Metabolism Using Tandem 

Spectrometry: A Systematic Review,” Health Technology Assessment 8 (2004): 

50 ACMG, Newborn Screening, p. 8. 
It may indeed be ethically problematic to withhold clinically 

cant test results for the secondary conditions, even if they 

included in the screening panel only because they show up 

of the differential diagnosis of core conditions. For most o

conditions, however, the clinical significance of a positive scr

result is very much in doubt. And it is necessary to consid

consequences of informing physicians and parents that a ch

been identified as having a serious genetic disorder, when th

ral history of that disorder is poorly understood and the appr

treatment—or even the need for treatment—is highly uncerta

An instructive case is Wisconsin’s experience with the organ

disorder 2-methylbutyryl-coenzyme A dehydrogenase deficie

MBG), now included in the ACMG’s secondary panel becau

part of the differential diagnosis (by MS/MS) of the core con

IVA.52 As of November 2008, forty-three states were scr

newborns for 2-MBG. Outside of the United States, only a h

                                                      

51 Ibid., pp. 11, 20, 62, 75. Rodney Howell (“We Need Expanded N

Screening,” p. 1801) says that the ACMG’s experts felt strongly that any 

abnormality revealed by the secondary screening panel “should not be 

cret” from the child’s physician and parents. He contrasted this approa

that of the German screening program, “in which information about co

not listed on their panel would not only be withheld but that the info

should be destroyed.” According to Rodney J. Pollitt, in 2004 the Germ

eral Ministry for Health and Social Security approved screening newbo

fourteen disorders, but the government also forbade screening for any ot

dition and “decreed that accidentally obtained results arising from the 

screens must be ignored and not communicated to anyone. All blood-sp

ples are to be destroyed within three months.” Rodney J. Pollitt, “Inter

Perspectives on Newborn Screening,” Journal of Inherited Metabolic Di

(2006): 390-396, p. 392. 

52 Sandra C. van Calcar, et al., “2-Methylbutyryl-CoA Dehydrogenase De

in Hmong Infants Identified by Expanded Newborn Screen,” Wisconsin 

Journal 106 (2007): 12-15. We are grateful to Norman Fost for bringing t

to our attention. 
in 2000, added 2-MBG to its mandatory newborn screening 

Surprisingly, over the next six years, twenty-seven Wisconsin 

were identified with 2-MBG, all but one of whom were offsp

Hmong parents.53 Most of these infants were put on a diet 

protein and supplemented with carnitine, although parental c

ance with this diet was quite variable. In any event, as of 200

the Wisconsin children who had been diagnosed at birth with 2-MB

normal, healthy, and asymptomatic. It is at this point uncertain w

the restrictive diet was effective, whether the genotypic varian

MBG shared by Hmong infants is essentially benign, and w

infants identified at birth with 2-MBG ought to be treated pre

tomatically at all. What is clear is that nationwide screening 

MBG, as recommended by the ACMG, will result in a sign

number of children (mostly of Hmong descent) being labeled 

serious illness, despite the fact that the majority of them mi

main asymptomatic even without any treatment. 

We cannot say how typical the case of 2-MBG is of the con

on the ACMG’s secondary screening panel. However, with t

five of these rare and poorly understood disorders being pro

to the states for mandatory screening, and with more presu

on the way as the panel of primary conditions expands furth

number of American children in this doubtful situation seem

tined to grow considerably. In addition to the possibility o

treating (and possibly harming) children who are healthy, the

                                                      

53 Van Calcar, et al., estimate that, in Wisconsin, 2-MBG has a preva

1:223 among Hmong infants, but only 1:325,593 among white newborns. 

Calcar, et al., “2-Methylbutyryl-CoA Dehydrogenase Deficiency in Hm

fants Identified by Expanded Newborn Screen.” As of 2008, eighty-one 

2-MBG had been identified in the United States, seventy-two of them in 

sin and Minnesota, where large Hmong populations have settled

downloaded from the National Newborn Screening Information System

able online at www2.uthscsa.edu/nnsis.) 
 So far, at least, it would appear that the recommendation to 

for a panel of secondary conditions—poorly understood, not 

treatable, or both—is merely an artifact of the way some p

conditions are detected, an unfortunate necessity that co

avoided altogether if there were a way to screen only for t

mary condition. Only twenty of the twenty-five sec

conditions, however, were included in the panel on this basis. 

spelled out fully, the ACMG’s standard for including a condi

the secondary panel is that the condition must be either “part 

differential diagnosis of a primary target condition” or mere

parent in the result of the multiplex assay.”55 In fact, five con

were evidently added to the secondary panel on this less st

basis.56 Each of these five conditions is very far from meeti

classical standards for inclusion in a newborn screening progr

                                                      

54 On parental attitudes toward the “vulnerable child,” see Morris Gr

Albert J. Solnit, “Reactions to the Threatened Loss of a Child: A Vu

Child Syndrome,” Pediatrics 34 (1964): 58-66; Morris Green, “Vulnerab

Syndrome and Its Variants,” Pediatrics in Review 8 (1986): 75–80; and 

Thomasgard and W. Peter Metz, “Parental Overprotection and Its Rel

Perceived Child Vulnerability,” American Journal of Orthopsychiatry 67 (199

335. According to Thomasgard and Metz, families of children who re

from a potentially fatal medical condition were found “to share a num

characteristics that centered on the marked discrepancy between the chil

mal health, growth, and development, and the parent’s unfounded belief 

child continued to be at risk for serious illness and was destined to die 

turely.” 

55 ACMG, Newborn Screening, p. 9. 

56 Ibid., p. 64. The report indicates that only four rare conditions were 

into the secondary target panel for this reason (viz., that they are detecta

multiplex assay, although detecting them is not required for the different

nosis of any primary condition): the fatty acid oxidation disorders Sho

acyl-CoA dehydrogenase deficiency (SCAD) and Dienoyl-CoA reducta

ciency (DE-RED), the organic acid disorder Isobutyryl-CoA dehydr

deficiency (IBG), and the amino acid disorder Argininemia (ARG). But it 

that the organic acid disorder Malonic acidemia (MAL) also was include

secondary panel on this basis. 
y g

comments that “the sensitivity and specificity of the primary 

are also unknown,”57 as are the availability, cost, and potenti

cacy of any treatment. DE-RED is not detected as part 

differential diagnosis of any other condition; nonetheless, 

because it is possible to detect DE-RED using MS/MS, the A

report recommends that DE-RED screening be included 

mandatory (secondary) screening panel in all fifty states. As 

vember 2008, newborn screening for DE-RED was manda

law in sixteen states and offered in three others. 

D. The Role of Multiplex Screening Platforms 

To understand why these five rare, poorly understood con

were included in the ACMG’s secondary target category, it is 

sary to delve more deeply into the technology of prese

newborn screening. Some conditions that are candidates fo

born screening are identified by way of unique 

methodologies, but many can be detected using multiplex pla

that screen simultaneously for several conditions. Of the t

nine core conditions, twenty-three are identified using mu

platforms: MS/MS for the six amino acid disorders, the n

ganic acid disorders, and the five fatty acid oxidation disorde

either high pressure liquid chromatography (HPLC) or isoe

focusing (IEF) for the three hemoglobinopathies. Only six 

core conditions require unique “singleton” tests.58 Of the t

five secondary conditions, all but two are detectable using mu

platforms.59 

                                                      

57 Ibid., p. 233. 

58 Ibid., p. 10. The six exceptions are CH, BIOT, CAH, GALT, hearing l

CF. 

59 Those two are the carbohydrate disorders galactokinase deficiency 

and galactose epimerase deficiency (GALE), conditions included in the se

panel because they are a part of the differential diagnosis of GALT. 
y g 

multiple different disorders. Going from one test for o

disorder to one test for multiple disorders has the pote

tial to reduce costs per condition tested and can lead 

test expansion if these new technologies can be integrat

safely and effectively into newborn screening programs.60

The report notes that, with some multiplex platforms, the sc

must select specific targets for inclusion in the test (this is kn

“selective reaction monitoring” or SRM), while for others t

automatically screens for multiple targets without the need fo

cific target selection (this is known as “full profile test

MS/MS in particular can be used in either selective or full 

mode.62 Selective monitoring means using the multiplex platf

target only those conditions deemed appropriate for screening. In contra

full profile approach means making maximum use of the te

ogy’s information-gathering powers, without regard to the dis

between appropriate and inappropriate target conditions. 

Remarkably, the ACMG report makes a forceful case that, 

ever possible, MS/MS screening should be carried out in full 

mode. The report gives several reasons for this judgment, 

which is simply that “the use of MS/MS profiles allows f

maximal use of the technology for the identification of cl

significant conditions.”63 Elsewhere the report extols “the in

                                                      

60 Ibid., pp. 18-19. 

61 Ibid., p. 19. An example of selective multiplex screening is the use o

chips” to test for the presence of a specific set of single nucleotide p

phisms (SNPs) in the human genome; an example of full profile testing i

sequencing of the entire genome. 

62 Ibid., pp. 19, 60-61. 

63 Ibid., p. 61. The other reasons are the following: 1) Most of the othe

tions identifiable by MS/MS are already required for the differential diag

the high-scoring core conditions; thus full profile screening ensures that 

conditions are diagnosed with the maximum specificity and sensitivity. 2) 
Although information about conditions for which trea

ment options are scarce or not yet reported can lead 

increased stresses on families and the health care system

early information can also lead to knowledge of the cond

tion for the family, thus avoiding a potential diagnost

odyssey or inappropriate therapies. In addition, early inf

mation provides opportunity for better understanding of disea

history and characteristics, and for earlier medical interventions th

might be systematically studied to determine the risks and benefi

Multiplex testing and the identification of conditions falling outside 

the uniform screening panel provides the opportunity for such con

tions to be included in research protocols.

65

In other words, screening for a condition that fails to meet th

sical criteria can be justified under a broadened conception of bene

includes not only helping the family avoid “the diagnostic od

but also helping society by providing opportunities for biomed

search aimed at understanding the natural history of the disord

finding an effective treatment for it. 

E. A Broadened Conception of Benefit 

The ACMG’s emphatic preference for the use of multiple

forms in “full profile” mode is thus indicative of a broa

conception of benefit that could justify screening for near

condition. Traditionally, as we have seen, the only relevant 

                                                                                                          

ing all information to be assessed can reveal the presence of spurious 

and/or contaminants.” 3) Full profile testing can “enhance clinical interp

of results by revealing anomalies in associated compounds or in compou

provide internal standards against which excesses or deficiencies can b

interpreted.” 

64 Ibid., p. 51. 

65 Ibid., p. 20; emphasis added. 
gg y 

the individual screened (chiefly when there is a known and ef

treatment), but they also gave weight to “benefits of early int

tion for family and society”: 

Families could benefit from establishing that there may 

a genetic risk to others in the family. Society could bene

by a reduction in medical diagnostic odysseys that a

costly to the healthcare system.66

Elsewhere, the report makes clear that the societal benefits of ne

screening include the opportunity for progress in biomedical res

Thus, it seems clear that, in extolling the advantages of mu

platforms and in calling for their use in “full profile” mode—

when some of the conditions detected are rare, poorly unde

and as yet untreatable—the ACMG working group was th

more broadly about benefits to family and to society, and esp

about the value of studying rare and obscure disorders in order to und

them and to find an effective treatment. 

F. Impact of a Broadened Conception of Benefit on 

ACMG Recommendations 

The impact of this broadened conception of benefit on the A

working group’s final recommendations can be seen in two 

ent places: in the initial scoring of the conditions that assigned 

                                                      

66 Ibid., p. 43. On expansive notions of benefit in the ACMG’s report, 

Donald B. Bailey, Jr., et al., “Changing Perspectives on the Benefits of N

Screening.” 

67 Note the phrase “understanding prevalence and natural history” in Ta

page 44 of the ACMG’s report, as well as the earlier reference, on page 2

“opportunity for better understanding of disease history and characteris

for earlier medical interventions that might be systematically studied to de

the risks and benefits.” 
g

asked a series of questions and assigned points to each con

based on the answers of hundreds of experts. With extrem

vorable answers from the experts, a condition could s

maximum of 2,100 points. Of these, up to 700 points were aw

to a condition based on some of the main attributes of the 

tion (incidence, burden if untreated, benefits of intervention

up to 700 points for attributes of the screening test (sens

specificity, multiplex versus singleton, etc.), and up to 700 

for aspects of treatment and management (availability, cost, e

etc.). Among many other criteria, up to 200 points were awar

a condition for evidence of “individual benefits of early int

tion.” But up to 100 points were awarded to a conditi

evidence of “family and societal benefits of early interve

Moreover, another 200 points were awarded to a condition 

being detectable using a multiplex platform, and fifty additional 

were awarded to a condition if, in the course of detecting it

conditions were also identified. In other words, a condition 

well be bumped up to the middle- or even to the high-scorin

sion despite showing scant evidence of benefit to the ne

child. 

After the initial scoring, the eighty-four conditions we

evaluated using a decision tree that is depicted in Figure 9 

ACMG report (reproduced below). High-scoring (>1,200) 

tions were added to the core panel if, on further review, e

determined that a treatment was available and necessary an

the natural history of the disease was well understood. Bu

scoring conditions for which there was no treatment still en

in the secondary panel if they were part of the differential dia

of a core condition, or even if they were merely detectable as part of 

plex assay in full profile mode. If a treatment was available b

natural history of the disease was poorly understood, the 

scoring condition still ended up in the secondary panel. And i
y 

the mandatory screening panel; it merely led to the disease be

classified as a secondary rather than a primary target. 

Meanwhile, middle-scoring conditions (1,000-1,200) were ad

the secondary panel as long as they were part of a differentia

nosis or were detectable by multiplex assay. And even low-s

conditions (<1,000) were to be bumped up to the secondary 

if they were detectable in a multiplex assay.69 In this regar

worth noting that the ACMG working group considered for 

sion but ultimately rejected the rare lysosomal storage dis

Fabry, Krabbe, Pompe, and Hurler-Scheie, scores of which 

from 447 to 707. These extremely low scores reflect not on

absence, at present, of a sensitive and specific screening te

also the unavailability of any effective treatments. Neverthele

searchers are well on their way to developing MS/MS assa

these conditions,70 and the ACMG report’s decision tree 

seem to dictate the automatic inclusion of all these untreatab

poorly understood disorders (and related disorders su

Gaucher, Hunter, Niemann-Pick, and Tay-Sachs) in the sec

panel as soon as it becomes feasible to detect them using a 

plex platform such as MS/MS. 

                                                      

68 Ibid., p. 64. In fact, all three of these conditions are identified as par

differential diagnosis of one of the core conditions, so they would have 

cluded in the secondary panel regardless of their survey score. 

69 In fact, no condition scoring <1,000 was moved to the secondary pane

basis; the lowest-scoring condition in the secondary panel is Citrullinemia 

(CIT-II, score 1,001), included because it is in the differential diagnosis o

linemia type I (CIT-I). However, it is to be noted that, of the thirty d

specifically excluded from screening, fully twenty-three of them were 

simply because no reliable test is currently available. Many of these condition

presumably be moved into the secondary panel (and some even to the cor

if a test became available, especially if it were part of a multiplex assay. 

70 See the references in Chapter One, Footnote Thirteen.
Copyright© American College of Medi

Unauthorized reproduc

                                                      

71 Ibid., p. 121. 
pppy pp

as far as the infant and family are concerned. If a state screening pr

embraces the ACMG’s recommendation of mandatory screen

both primary and secondary conditions (and most states seem 

on their way to doing so), a positive screening result is repo

the physician and the family regardless of the target categ

which the condition happened to be included. With this in 

the ACMG report’s decision tree seems to depart much mor

cally from classical screening principles than it first appeared t

As noted above, the twenty-nine core conditions were each j

by the ACMG working group to meet the traditional stand

having 1) a specific and sensitive screening test, 2) a sufficient

understood natural history, and 3) an available and effic

treatment. Moreover, for twenty of the twenty-five secondar

ditions, screening could be considered justified on the groun

it was necessary for the differential diagnosis of one of th

conditions. Only five exceedingly rare conditions were added 

secondary panel without that compelling justification. Seen 

light, the expansion in newborn screening recommended 

ACMG would appear to be rather moderate and fairly con

with accepted screening principles. 

But a careful examination of the ACMG working group’s d

tree—and, above all, of its procedures for adding conditions 

secondary panel—makes it clear that the foundations have be

for a much more radical expansion of newborn screening in 

ture, and for a significant loosening of the traditional scr

standards. Under the ACMG’s procedures, a rare and poorly 

stood genetic condition, even one with no available treatme

routinely be added to the secondary target panel (recommend

mandatory screening in all fifty states) as soon as it becomes 

ble to detect that disorder using a multiplex assay in full 

mode. Even if only a handful of conditions have so far qualif
In brief, it seems fair to conclude from a careful reading of 

port that the ACMG working group has effectively recomm

mandatory newborn screening for two categories of conditio

relatively small number of treatable and well understood dis

that satisfy the classical Wilson-Jungner criteria, and the pot

much larger set of untreatable and poorly understood disorde

fall short of those criteria but are detectable by multiplex scre

If the chief purpose of screening conditions in the former ca

is to benefit the affected newborn with timely and effective 

ment, the chief purpose of screening conditions in the 

category would seem to be to advance the scientific study 

disorder, with the ultimate goal of finding an effective trea

That is certainly a laudable goal, but as a basis for including 

tions in a mandatory newborn screening panel it represents a 

departure from the principles expressed in the Wilson-Jungn

teria. Hitherto, for diseases that were poorly understood 

which no effective treatment was available, we as a nation ha

been in the habit of subjecting individuals to compulsory scr

merely for research purposes. In the wake of the ACMG repo

its enthusiastic reception by the states, our approach to ne

screening seems to be heading into uncharted territory. 

\[

51

THE FUTURE OF NEWBORN 

SCREENING 

n the previous chapter, we considered certain urgent eth

lemmas that confront us today as the states proceed to e

their mandatory newborn screening programs. In this c

we lift our eyes from the present scene and contemplate how 

born screening may continue to evolve as the age of ge

medicine advances. Over the next years and decades, antic

developments in the technology and the practice of medic

likely to alter the landscape of newborn screening entirely, us

in a potentially vast increase in the kinds and amounts of 

data that can be routinely collected upon the birth of a child

quite possible that today’s debates over whether to add this 

rare disorder to a uniform screening panel will be swamped, 

context of genomic medicine, by a radically more expansi

proach to genetic screening. It is the burden of this chap

sketch some of the possible consequences for newborn scr

and to outline the serious ethical dilemmas that we are likely 

in the future. 

This chapter has three parts, addressing the following topic

newborn screening in the age of genomic medicine; secon

case for newborn profiling; and third, the case for caution. 

                                                      

1 And not only genetic data: the medically relevant information that will 

lected is likely to embrace both “epigenetics,” the systematic study of h

but non-genetic factors that influence an organism’s development, an

teomics,” the systematic study of the full complement of an organism’s 

(“proteome” being a word formed by analogy with “genome”). 

I
ppg

conditions, from rare genetic disorders to common illnesses. O

basis of comprehensive genomic knowledge, it is believed th

sicians of the future will be able to tailor diagnosis and treatm

the unique genetic profile of the individual patient, thereby eli

ing much of the guesswork of traditional “one size fits all” m

practice. 

To achieve its full potential, personalized medicine will requir

sicians to gather large amounts of genetic information from 

patients. The National Human Genome Research In

(NHGRI) has announced the goal of reducing the cost of se

ing an individual human genome first to $100,000 and t

$1,000. At this last price point, thought to be reachable by 20

individual’s full genome could be added to his or her medical 

part of routine medical care—to supplement and in some w

supersede the patient’s family medical history. The $1,000 g

may arrive sooner than even this optimistic projection wou

gest. In 2007, the complete genome of geneticist and co-disc

of the double helix James D. Watson was sequenced at a c

about $2 million;2 in the fall of 2008, a company in Californ

nounced plans to begin offering complete human g

sequences for $5,000, starting in the spring of 2009.3

In the meantime, it is already feasible, using “gene chips

crobeads, and other state-of-the-art multiplex technologies, 

an individual’s DNA for the presence of hundreds of thousa

                                                      

2 The company that sequenced Watson’s DNA is called “454.” See Emily 

“The $2 Million Genome,” Technology Review, June 1, 2007. 

3 The company is called Complete Genomics, and its website is www.com

enomicsinc.com/. See Emily Singer, “Five Thousand Bucks for Your Gen

New Sequencing Service Could Change the Face of Human Genomics,” 

ogy Review, October 6, 2008; and Erica Check Hayden, “$5,000 Genom

Year, Company Promises,” Nature News, October 6, 2008. 
yg

late with particular traits, conditions, and susceptibilities.5 C

the genomic era is already upon us. 

Rapid medical and technological progress aided by the Hum

nome Project is challenging both the practice and the princi

newborn screening. As mentioned, most babies born today 

United States are screened at birth for between thirty and fi

netic disorders, primarily by using MS/MS to detect abnorma

of metabolites in the infant’s blood. At the same time, the N

Institute of Child Health and Human Development (NICH

spearheading efforts to move beyond such limited, phen

methods of newborn screening toward DNA-based platform

can “offer enormous opportunities to identify staggering nu

of potentially pathogenic mutations in a very large number 

ease-associated genes.”6

 Many competent observers expect t

                                                      

4 Gene chips are glass or silicon chips to which are bonded thousands o

scopic spots containing short DNA sequences called oligonucleotides. Ea

serves as a probe to detect the presence of a particular SNP in the targ

sample. The leading developer of gene chips is a company called Affymet

other approach is to bond the oligonucleotide probes to thousa

microscopic silica beads, which are then randomly deposited onto a gl

strate. The resulting array is then used to check the target DNA sam

particular SNPs. A company called Illumina has pioneered the use of micr

5 See, for example, the websites www.23andme.com and www.decodem

each of which offers to test a client’s DNA for several hundred thousand 

SNPs. See Robert F. Service, “Gene Sequencing. The Race for the $10

nome,” Science 311 (2006): 1544-1546; and Sarah E. Gollust, et al., “D

Consumer Sales of Genetic Services on the Internet,” Genetics in Medicine 5 

332-337. For a thoughtful discussion of some ethical and legal implication

$1,000 genome, see John A. Robertson, “The $1000 Genome: Ethical an

Issues in Whole Genome Sequencing of Individuals,” American Journal of 

3 (2003): W35-W43. 

6 Duane Alexander and James W. Hanson, “NICHD Research Initiative 

born Screening,” Mental Retardation and Developmental Disabilities Research R

(2006): 301-304, p. 302. 
two decades and thus one of the nation’s leading voices in pe

medicine, coauthored an article with his colleague Peter van 

offering their “vision of the future of newborn screening.”8 

article, Alexander and van Dyck refer to the principle that “i

propriate to screen only for conditions for which ef

treatment already exists” as a dogma that “dooms us to con

ignorance and unavailability of treatment because affected in

als are not identified until they exhibit symptoms, too la

effective preventive interventions to be tested or applied.”

call for the development and implementation of DNA-based 

plex platforms that can be used to screen newborns for “virtu

target conditions with one test system.”10 More fundament

their view every medically significant genetic marker should 

sumed to be screenable except those specifically excluded on a case

basis.

11 Assuming that in a matter of years or at most decad

                                                      

7 Nancy S. Green and Kenneth A. Pass, “Neonatal Screening by DNA M

ray: Spots and Chips,” Nature Reviews Genetics 6 (2005): 147-151. 

8 Duane Alexander and Peter C. van Dyck, “A Vision of the Future of N

Screening,” Pediatrics 117 Supplement (2006): S350-S354. 

9 Ibid., pp. S351, S352. 

10 Ibid., p. S351. In his presentation before this Council on June 23, 20

Alexander elaborated: “[Tandem mass spectrometry] still doesn’t go as f

need it to go. And so we’re looking at potential DNA-based systems. If w

have this, we could screen for basically anything we have the gene fo

numbers go into the hundreds. And each time we discover a new gene o

abnormality of a gene the number of conditions would go up. 

 “...[T]hese are things that are coming along and that we are inve

trying to develop an enhanced capability to screen, and to have a test th

attractive, so simple, and not too expensive, so that every state will wan

this in their screening program, and no longer will there be this state

variability, so that what you get screened for depends on the state in whic

born.” (For an online transcript of Dr. Alexander’s remarks, see www.bio

gov/transcripts/june06/session5.html.) 

11 In their article, Alexander and van Dyck mention only Huntington’s dis

invariably fatal, as yet untreatable, adult-onset, Mendelian dominant, neur
y y p

otherwise to be enrolled in registries to await trials of experi

therapies. Personalized genomic medicine will then start fro

moment of birth, as the pediatrician will be in possession of 

plete map of each young patient’s known genetic d

vulnerabilities, and susceptibilities. In what follows, we shall 

this vision of a vastly expanded screening program by the 

“newborn profiling.”12

Thus, in contemplating the future of newborn screening, Ale

and van Dyck are calling for the old “dogma”—“screen only 

can effectively treat”—to be superseded by a new princ

“screen unless there is a compelling reason not to screen.” 

radical change in the ethical framework of newborn screening 

seem far-fetched today, but in some ways the ground for it 

ready been prepared by the ACMG in its 2005 report. As des

in the preceding chapter, the ACMG report’s recommended 

sion in newborn screening quietly incorporates the principle 

conditions that can be detected by multiplex assay should be included 

mandatory screening panel, regardless of whether or not they meet the tra

Wilson-Jungner criteria. The fact that, in the ACMG report, thi

ciple led to the inclusion of only a handful of rare dis

                                                                                                          

disorder) as a possible candidate for exclusion. (“A Vision of the Future o

born Screening,” p. S353.) It is not clear what other disorders they woul

the same category. At Duane Alexander’s June 23, 2006, appearance be

Council, Council Member Floyd Bloom pointed out that Huntington’

seem to fulfill “all of the criteria by which you listed the tests that you 

include, even though we can’t treat them.” (See www.bioethics.gov/transc

june06/session5.html.) If a new treatment were developed that, when 

early in life, produced even a modest decrease in the morbidity or mor

Huntington’s disease, it is reasonable to suppose that Alexander and va

would move Huntington’s into the “screen” column. 

12 We borrow this informative phrase from the 2005 report, Profiling the N

A Prospective Gene Technology?, published by the Human Genetics Commi

the United Kingdom, available online at www.hgc.gov.uk/. 
pppp

look at each in turn. 

II. The Case for Newborn Profiling 

Given that the current debate is mostly about whether to ad

or that disorder to the limited panel of conditions for which 

borns are routinely screened, why should we believe that 

future the default practice could be to screen all newborns f

known genetic abnormality? The short answer is this: because 

of personalized medicine and of technological progress will inexorably dem

A. The Logic of Personalized Medicine and 

 Technological Progress 

In 2001, Francis Collins, who led the Human Genome Projec

1993 to 2008, described what genomic medicine would look 

its earliest stage: 

By the year 2010, it is expected that predictive genetic tes

will be available for as many as a dozen common cond

tions, allowing individuals who wish to know th

information to learn their individual susceptibilities and 

take steps to reduce those risks for which interventions a

or will be available. Such interventions could take the for

of medical surveillance, lifestyle modifications, diet, 

drug therapy. Identification of persons at highest risk f

colon cancer, for example, could lead to targeted efforts 

provide colonoscopic screening to those individuals, wi

the likelihood of preventing many premature deaths.13

                                                      

13 Francis S. Collins, “Implications of the Human Genome Project for 

Science,” Journal of the American Medical Association 285 (2001): 540-544, p

544. 
gy p

just the time at which colonoscopy should commence 

specific genome of the patient, thereby catching many cancer

earlier, treatable stage. In principle, the same sort of adjustm

routine screening schedules will be possible when screeni

other cancers, tremendously improving the odds of detectin

eliminating those cancers before they turn deadly. As renown

stetrician-gynecologist Alan Guttmacher and colleagues 

“genomics-based knowledge and tools promise the ability 

proach each patient as the biological individual he or she is, t

radically changing our paradigms and improving efficacy.”14 

The drive toward unlimited expansion of newborn screeni

also be fueled by technological progress, which has given 

MS/MS—a method of screening for dozens of metabolic dis

at once, and which will soon deliver—in the form of DNA

multi-array platforms—the ability to screen whole genomes f

or hundreds of thousands of medically significant markers. 

observers believe that a “technological imperative” in moder

ety (combining a desire for commercial profit with a beli

“knowledge is power” and that “if we can do it, we should”) 

it inevitable that maximal use of genomic information will b

part of the medical practice of the future.15

Once personalized genomic medicine becomes standard m

practice for adults, the logic of providing physicians with thi

erful tool earlier and earlier in the patient’s life may 

                                                      

14 Alan E. Guttmacher, et al., “Educating Health-Care Professionals abou

ics and Genomics,” Nature Reviews Genetics 8 (2007): 151-157. 

15 On the “technological imperative” in modern medicine, see Evan Will

‘New’ Genetics and the Sociology of Medical Technology,” Journal of Soc

(1998): 170-183; Daniel Callahan, What Price Better Health Care? Hazards o

search Imperative (Berkeley: University of California Press, 2003); and Arnol

The Culture of Technology (Cambridge, Massachusetts: MIT Press, 1985). 
will become more generally available, and many primary car

cians will become practitioners of genomic medicine...”17 B

so many of our habits are formed in childhood, there will be 

pelling reasons for pediatricians to become genomic practitio

well. To fulfill its promise of predictive and preventive as 

personalized care, genomic medicine will push the point of da

lection to the moment of birth—if not earlier. 

B. The Benefits of Biobanking 

Biobanks, which are huge repositories of tissue samples or 

information that interlink human genotypes with lifelong m

histories, could help us make use of the large quantities of 

data collected from newborns.18 Biobanks at present are ty

considered to be research enterprises, but, under the rubric 

nomic medicine, it seems likely that in the future they will mo

more become a tool for the clinician, a sort of “family histor

                                                      

16 On the other hand, there is some evidence that DNA risk information 

less likely to achieve behavior change than other types of health risk info

See Theresa M. Marteau and John Weinman, “Self-Regulation and the 

ioural Response to DNA Risk Information: A Theoretical Analy

Framework for Future Research,” Social Science and Medicine 62 (2006): 1360

17 Francis S. Collins, “Implications of the Human Genome Project for 

Science,” p. 544. 

18 See Dan M. Roden, et al., “Development of a Large-Scale De-Identifie

Biobank to Enable Personalized Medicine,” Clinical Pharmacology and Therap

(2008): 362-369. Some countries are or will soon experiment with large-sc

banks. One example is the UK Biobank, whose database will cover 

volunteers and will interlink their health, lifestyle, and environmental 

with gene maps of DNA extracted from their blood. See their we

www.ukbiobank.ac.uk. An even more ambitious genomic biobank, inte

include the entire population of Iceland, was inaugurated by an act of 

landic parliament in 1998, but has subsequently been scaled back conside

the face of legal and ethical controversy. See Henry T. Greely, “Iceland’s 

Genomics Research: Facts and Implications,” Jurimetrics 40 (2000): 153-19
p

and susceptibilities.20 

Here, too, the logic of personalized medicine dictates that t

lection of genotypic data and its correlation with individual m

environmental, and lifestyle histories should cover the whole 

lifespan, not excluding adolescence, childhood, birth, and eve

tation in the womb.21 Moreover, the day of their birth is ar

the most convenient opportunity to enroll children, with the 

eration of their parents, in the comprehensive data-gathering 

on which their personalized medical care will be predicated. I

pediatric biobanks are already being established in this count

it stands to reason that the most powerful and useful form o

                                                      

19In the United States, the “Genomics and Personalized Medicine Act o

sponsored in the 110th Congress by then Senator (and now Presiden

Barack Obama in order “to secure the promise of personalized medicin

Americans by expanding and accelerating genomics research and initia

improve the accuracy of disease diagnosis, increase the safety of drugs, a

tify novel treatments,” calls for the establishment of “a national bio

distributed database for the collection and integration of genomic data, a

ciated environmental and clinical health information, which shall 

synthesis and pooled analysis of such data.” The text of the proposed le

may be found online at www.govtrack.us/congress/billtext.xpd?bill=s110

 On the prospects for a large-scale U.S. biobank, see also the Mar

report of the Secretary’s Advisory Committee on Genetics, Health, and 

Policy Issues Associated with Undertaking a New Large U.S. Population Cohort 

Genes, Environment, and Disease (Bethesda, Maryland: U.S. Department of 

and Human Services, 2007), available online at www4.od.nih.gov/oba/sac

reports/SACGHS_LPS_report.pdf.

20 See Kaare Christensen and Jeffrey C. Murray, “What Genome-Wide A

tion Studies Can Do for Medicine,” New England Journal of Medicine 356 

1094-1097. 

21 However, for a study of the legal and ethical problems posed by the e

ment of genotypic databases, see Henry T. Greely, “The Uneasy Eth

Legal Underpinnings of Large-Scale Genomic Biobanks,” Annual Review o

ics and Human Genetics 8 (2007): 343-364. 
pgy p

year are more difficult to study than more common diseases 

victims are easy to locate and study. An obscure illness for 

there is as yet no treatment is more likely to be elucidated an

liorated or cured if newborn screening gives the medical com

an accurate picture of the prevalence of the disorder as well a

access to as many of its sufferers as possible. Genomic m

offers a compellingly systematic approach to the search for 

ment of such illnesses, including the following methodical 

comprehensive genetic profiling at birth, followed by enrollm

all afflicted patients in a biobank of genotypic data; careful st

the course of the illness in each patient, with all significant m

histories entered in the biobank; and finally, when innovative 

pies become available, easy access to pools of potential re

subjects, to be contacted and enrolled in experimental trials 

are willing. Surely it will be seen to be in the patients’ in

broadly understood, to push their incurable genetic ailmen

the column of treatable illnesses, even if no actual treatment i

able at the time of their diagnosis. 

C. The Psychosocial Consequences of Testing Posi

A Silver Lining? 

With comprehensive screening, there is hope that the psych

consequences of testing positive for a genetic ailment will 

                                                      

22 See Jocelyn Kaiser, “U.S. Hospital Launches Large Biobank of Ch

DNA” (News of the Week: Genetics), Science 312 (2006): 1584-1585. Ac

to Kaiser, Children’s Hospital of Philadelphia plans “to analyze DN

100,000 children and begin searching for links to childhood diseases 

asthma, diabetes, and obesity.” See also Alon B. Neidich, et al., “Empiri

About Women’s Attitudes Towards a Hypothetical Pediatric Biobank,” A

Journal of Medical Genetics Part A 146A (2008): 297-304; and David Kaufma

“Ethical Implications of Including Children in a Large Biobank for G

Epidemiologic Research: A Qualitative Study of Public Opinion,” Ameri

nal of Medical Genetics Part C: Seminars in Medical Genetics 148C (2008): 31-39
pggg

admittedly compromised when parents (or state governments

the decision to have children genetically screened.23 

But a case can be made that, with the full flourishing of ge

medicine and the routine gathering of thousands of data 

from every human genome, the stigma attached to most 

defects will largely dissipate, and along with it some of the m

vere psychological sequelae. It will be better understood the

every one of us, without exception, carries a multitude of 

genetic variations, some of them favorable to health and hap

others less auspicious. The sense that we are all in the gene

tery together, and no one is simply a winner or a loser, ma

provide the best foundation for a healthy and realistic attitu

ward the vicissitudes of inheritance. This is not to say th

discovery that one carries a fatal or incapacitating gene defe

the trinucleotide repeats that cause Huntington’s, will be e

bear, but it does suggest that a comprehensive transformat

American medicine in the genomic direction will render gene

ease as a whole less horrifying and isolating.24

                                                      

23 See Rony E. Duncan, et al., “‘You’re One of Us Now’: Young People D

Their Experiences of Predictive Genetic Testing for Huntington Disea

and Familial Adenomatous Polyposis (FAP),” American Journal of Medical 

Part C: Seminars in Medical Genetics 148 (2008): 47-55. 

24 On psychosocial risks and of comprehensive genomic testing of childr

pared to genetic testing, see Benjamin Wilfond and Lainie Friedman Ross

Genetics to Genomics: Ethics, Policy, and Parental Decision-making,” J

Pediatric Psychology, July 22, 2008 (epublication ahead of print), pp. 1-9; and 

W. Foster and Richard R. Sharp, “Ethical Issues in Medical-Sequencing R

Implications of Genotype–Phenotype Studies for Individuals and Popu

Human Molecular Genetics 15 (2006): R45-R49. 
gpp

knowing the diagnosis in the newborn period.”26 And indeed

ies have consistently shown strong (and growing) public supp

genetic screening, especially among parents of children with 

disorders.27 Parents in the latter group seem to believe tha

have a right to know whether their child has a genetic disorde

                                                      

25 Some of the same social pressures are at work in driving the states to o

maximal panel of conditions for newborn screening. As Jeffrey Botkin 

remarks to the Council on February 3, 2006, “I think there’s a strong so

tude that screening is a good thing, and I see it in the paper every morn

the body scanners. You know, spend 600 bucks. Detect disease early a

your life. Well, there’s no data to support any of that, but it’s part of th

consciousness now, and I think how that’s translated into newborn scre

the strong sense that if you’ve got five tests, that’s good. If you’ve got 

that’s really terrific, and any self-respecting state, you know, should not h

than 40 tests on its panel.” (Remarks available online at www.bioethics.go

cripts/feb06/session6.html.) 

26 Duane Alexander and Peter C. van Dyck, “Neonatal Screening: Old D

Sound Principle?” (in reply), Pediatrics 119 (2007): 407. 

27 For example, Fragile X syndrome, the most common inherited form o

retardation, does not meet the criteria for routine newborn screening, as 

currently no cure or medical treatment. But in a recent survey of parents 

dren with Fragile X, large majorities (over ninety percent) favored s

newborns both for the genetic disorder and for carrier status. See Debra 

et al., “Screening for Fragile X Syndrome: Parent Attitudes and Persp

Genetics in Medicine 5 (2003): 378-384. 

 Another example: Although professional guidelines recommend agai

ing minors for adult-onset genetic conditions, medical oncologist and fam

assessment expert Angela Bradbury and colleagues found that, among 

who are carriers of the BRCA mutations (which correlate with increased 

breast cancer) and their adult children, as many as forty percent supported 

testing of minors for the mutations. In fact, the adult children viewed such 

even more favorably than their parents, suggesting that succeeding gen

are growing more and more comfortable with the idea of routine genetic 

ing. See Angela R. Bradbury, et al., “Should Genetic Testing for BRCA

Permitted for Minors? Opinions of BRCA Mutation Carriers and The

Offspring,” American Journal of Medical Genetics Part C: Seminars in Medical 

148C (2008): 70-77. 
Such parents may be exhibiting a tendency that the French 

Alexis de Tocqueville noticed in Americans as long ago as 18

found that Americans are unwitting followers of the French 

alist philosopher, Descartes, in that they tend “to take traditio

as information, and current facts only as a useful study for 

otherwise and better; to seek the reason for things by them

and in themselves alone, [and] to strive for a result without 

themselves to be chained to the means.”30 In short, if their ch

                                                      

28 In a 1998 survey, North American parents (mostly mothers) of childr

diagnosed or unconfirmed genetic conditions were asked, “Some condit

be found at birth through a simple blood test. Sometimes there is no tr

for the child. In these cases, the main purposes of testing the newborn c

to find out if this child has a genetic condition and to let the parents kn

they could have another child with the same condition. If you were a 

would you want your newborn child tested right away so that you could 

if your next child would have a genetic condition?” Seventy-one perc

“yes,” eleven percent said “no,” and eighteen percent said “I don’t kno

Dorothy C. Wertz and John C. Fletcher, Genetics and Ethics in Global P

(Dordrecht, The Netherlands: Kluwer Academic Publishers, 2004), p. 

Dorothy C. Wertz, “Ethical Issues in Pediatric Genetics: Views of Gen

Parents and Primary Care Physicians,” Health Law Journal 6 (1998): 3-

conductors of the survey report that, “in write-in comments, parents s

had a right to know, that the information would help them relate to the

and that they wanted the information so they could decide about having 

child.” (Wertz and Fletcher, Genetics and Ethics in Global Perspective, p. 72) 

29 Surveying the general public on these questions, a 2007 report release

University of Michigan C. S. Mott Children’s Hospital National Poll o

dren’s Health found that fifty-four percent of adults endorsed genetic te

children even if no effective treatment is available, and thirty-eight pe

parents were willing to have their children’s DNA stored in a governmen

biobank. (Report available online at www.med.umich.edu/opm/newspage

NPCH_4.pdf.) 

30 Alexis de Tocqueville, Democracy in America, trans. Harvey C. Mansf

Delba Winthrop (Chicago: University of Chicago Press, 2000), Volume 2 

Part 1, Chapter 1, “On the Philosophic Method of the Americans,” p. 403
y gy gg

question. 

It would be difficult to exaggerate the role of patient ad

groups in pressing for the expansion of newborn screenin

March of Dimes Foundation president Jennifer Howse an

leagues put it, “Expansion of [newborn screening] has been 

primarily by a combination of advances in technology and m

treatment, and the sustained advocacy efforts of consume

voluntary health organizations.”33 University of North Carol

diatrician Donald Bailey and colleagues noted that, during 

commentary on the ACMG’s report, every advocacy grou

commented endorsed the uniform screening panel and n

range of benefits that would result from expanded scre

Moreover, “there was no mention of any risks or burd

screening other than to discount arguments that conditio

which there is no proven medical treatment for the child shou

be included in newborn screening.”34 Parents who discov

their newborn child suffers from a rare genetic illness are 

likely to add their support to groups calling both for un

screening and for increased funding of research to find a cur

doubtedly, such vigorous advocacy of newborn profiling m

good deal of sense under the paradigm of genomic medicine

                                                      

31 Pediatrician Kruti Acharya and colleagues found that “most physicians 

diagnostic genetic testing of high-risk children but are less supportive of 

ing newborn screening, particularly for conditions that do not meet the 

and Jungner criteria.” See Kruti Acharya, et al., “Pediatricians’ Attitudes 

Expanding Newborn Screening,” Pediatrics 116 (2005): e476-e484, p. e476

32 Diane B. Paul, “Patient Advocacy in Newborn Screening: Continui

Discontinuities,” American Journal of Medical Genetics Part C (Seminars in 

Genetics) 148C (2008): 8-14. 

33 Jennifer L. Howse, et al., “Critical Role of the March of Dimes in the 

sion of Newborn Screening,” Mental Retardation and Developmental D

Research Reviews 12 (2006): 280-287. 

34 Donald B. Bailey, Jr., et al., “Changing Perspectives,” p. 275. 
We have seen that there are powerful arguments—and poten

nological and social forces—favoring the eventual realization 

vision of universal DNA-based profiling of newborns, with 

netic markers of medical interest included by default, and p

only a handful of disorders excluded on a case-by-case bas

now turn to some of the reasons for doubting whether this v

likely to be realized, and whether—even if it is attainabl

benefits would outweigh the costs. In the long run, it may, 

prove impossible to hinder the logic of genomic medicine fr

similating the currently limited practice of newborn screening 

all-embracing paradigm. Nonetheless, even if these future de

ments turn out to be unstoppable, it would be prudent to r

ourselves of some of the reasons for doubting whether the n

gime of maximal screening will be altogether benign. We can 

approach the future with our eyes open, alert for signs o

amidst the progress. 

A. “Personalized Medicine” in the Traditional and 

 Increasingly Rare Sense 

As we have seen, there is some plausibility to the view tha

logic of personalized medicine” will inevitably push us in the 

tion of sequencing everyone’s genome as early as possible, an

lifetime clinical care will eventually consist of personalized p

tion and treatment strategies based on a detailed analysis 

patient’s genetic predispositions and susceptibilities. And yet

is an older and perhaps deeper notion of personalized medici

is likely to push back against the assumption that genome

health care will necessarily be better and more personal. 

sense, the personalized medicine that is most meaningful to p

is based on the physician’s knowledge of the patient’s medic

life circumstances and on the trusting relationship between 
y pgp

rithmic diagnosis and treatment. 

Of course, this is not to say that genomic information will n

a valuable part in future medical care. In some cases, ge

analysis will certainly alert the physician to health risks that 

not otherwise be evident from an examination of the patie

from knowledge of the family history. A realistic expectation 

be that, for any given health condition, a small minority of p

will benefit from knowledge about genomic risk—and that, w

breadth of information likely to be available, everyone wil

benefit from genomic risk information at some point—bu

much of health care will continue to proceed independently 

nomic risk profiling.36 On the whole, then, the goal of pro

personalized medical care in the older and perhaps more fund

tal sense of the term will continue to depend on the cha

                                                      

35 See Edmund D. Pellegrino and David C. Thomasma, For the Patient’s G

Restoration of Beneficence in Health Care (New York: Oxford, 1988); and D

Thomasma and Judith Lee Kissell, eds., The Health Care Professional As F

Healer: Building on the Work of Edmund D. Pellegrino (Washington, D.C.: Geo

University Press, 2000). 

36 On the other hand, the reality of medical practice in the current era i

which the physician’s time with patients is seriously compromised by 

demands, including the intrusive burdens of documentation and paperw

the financial imperative to “process” as many patients as possible in incr

abbreviated periods of time. Some argue that genomic medicine and info

technology will combine forces to alleviate this often distressing reality: i

tion technologies will simplify and speed the acquisition and proces

clinically relevant information, including genetic information, while the 

tion of genomic medicine itself will involve the use of genetic counselor

to the physician and will thereby ease the challenges of today’s one-on-

tient-physician encounters. See Kenneth M. Ludmerer, Time to Heal: A

Medical Education from the Turn of the Century to the Era of Managed Care (Ne

Oxford University Press, 1999); and Ralph Snyderman and R. Sanders W

“Prospective Medicine: The Next Health Care Transformation,” Academic 

78 (2003): 1079-1084. 
p 

patient and physician rather than on any particular tec

nology. Even in the genomic era, the focus on individu

patient needs and concerns will remain at the core 

health care; and if genetic testing diverts physicians’ atte

tions away from the specific concerns of the patient, 

may interfere with the practice of personalized medicine.

B. Doubts About the Power of Genomic Medicine 

Although many scientists and policymakers are confident tha

ies of the human genome will provide a wealth of v

information about health status and health risk in the near 

not all competent observers agree. In particular, doubts hav

expressed about the potential of genomic studies to find m

for susceptibility to the most common diseases afflicting ma

as opposed to the rare metabolic disorders that are the prima

get of newborn screening today. 

For example, the population geneticist David B. Goldstein ha

licly dissented from the idea that unlocking the human genom

lead to the discovery of common variants that predispose peo

various forms of cancer, heart disease, Alzheimer’s, and 

common major illnesses. This idea, known as the Commo

ease/Common Variant hypothesis, suggests that genom

                                                      

37 Wylie Burke and Bruce M. Psaty, “Personalized Medicine in the Genom

Journal of the American Medical Association 298 (2007): 1682-1684, p. 1684

and Psaty continue, “Personalized medicine has always been a compo

good medical practice. Genetic tests may provide new tools, but they 

change the fundamental goal of clinicians to adapt available medical t

technologies to the individual circumstance of their patients. As genetic t

come widely available, personalized medicine will include assisting pat

make wise use of genetic risk assessment, taking into account the cauti

cussed in this article. When genetic testing is used, the personalized natur

care will extend well beyond the patient’s base pair sequences.” 
pp pjy y 

that account for a disappointingly small portion of the gene

for disease. Goldstein said recently: 

 

There is absolutely no question, that for the whole hope 

personalized medicine, the news has been just about 

bleak as it could be... For schizophrenia and bipolar d

order, we get almost nothing; for Type 2 diabetes, 

variants, but they explain only 2 to 3 percent of famil

clustering, and so on... It’s an astounding thing that w

have cracked open the human genome and can look at t

entire complement of common genetic variants, and wh

do we find? Almost nothing. That is absolutely beyond b

lief.39

In a review of the recent achievements of genome-wide asso

studies, Goldstein and colleagues wrote the following: 

Despite understandable celebration of these achievemen

sober reflection reveals many challenges ahead... [F]

most of the traits studied, known variants explain only 

fraction of observed familial aggregation, limiting the p

tential for early application to determine individual disea

risk... The ultimate objectives—full descriptions of t

susceptibility architecture of major biomedical traits an

                                                      

38 On the Common Disease/Common Variant hypothesis, see David E

and Eric S. Lander, “On the Allelic Spectrum of Human Disease,” Trends 

ics 17 (2001): 502-510; and Neil Risch and Kathleen R. Merikangas, “The 

of Genetic Studies of Complex Human Diseases,” Science 273 (1996): 1516

39 See Nicholas Wade, “A Dissenting Voice as the Genome Is Sifted 

Disease,” The New York Times, September 15, 2008. 
It would be revolutionary if we could determine the gen

types of the majority of people who will get commo

diseases. The complexity of the genetics of common d

eases casts doubt on whether accurate prediction will ev

be possible... Although we do not contend that the genet

mantle is as imperceptible as the emperor’s new cloth

were, it is not made of the silks and ermines that som

claim it to be. Those who make medical and science po

cies in the next decade would do well to see beyond t

hype.41

Other experts remain optimistic, while acknowledging that t

benefit of the human genome project will take time to realize

it may well be that, for quite some time, detailed knowledge 

human genome will remain primarily useful for the diagnos

rare genetic disorders rather than for ascertaining a given in

ual’s susceptibilities to a large number of serious common illn

C. Newborn Profiling and the Problem of Risks and 

Benefits 

Many of the same concerns that have been expressed in reg

limited expansion of the newborn screening panel would a for

applicable in the case of newborn profiling. Norman Fost’s 

                                                      

40 Mark I. McCarthy, et al., “Genome-Wide Association Studies for C

Traits: Consensus, Uncertainty and Challenges,” Nature Reviews Genetics 9 

356-369. See also James H. Ware, “The Limitations of Risk Factors as Pr

Tools,” New England Journal of Medicine 355 (2006): 2615-2617. 

41 Neil A. Holtzman and Theresa M. Marteau, “Will Genetics Revol

Medicine?” New England Journal of Medicine 343 (2000): 141-144. 

42 See Alan E. Guttmacher and Francis S. Collins, “Welcome to the G

Era,” New England Journal of Medicine 349 (2003): 996-998. 
gg pg 

sessing the outcomes for the affected children. 

In clarifying the possible harms of gathering genetic infor

pre-symptomatically, it is important to distinguish the di

components of the problem: 

 

 First, such information may be clinically valid but n

practically useful. Detected genetic variations in the g

nome may suggest an elevated risk for a condition th

never actually develops, and to initiate treatment pr

symptomatically may do the patient more harm th

good.44 

 Second, genomic risk information that is assumed to 

valid may sometimes turn out to be unreliable—if, f

example, it is based on population studies that were to

small or that failed to take into account critical no

genetic variables.45 

 Third, there are the psychosocial effects of false po

tive results and, in the case of true positive results, 

adversely labeling the individual as suffering from d

ease from the moment of birth.46 

 Fourth, there is the danger that screening will lead to 

cascade effect—in which genetic risk information 

perhaps uncertain validity leads to additional tests an

                                                      

43 Norman Fost, “Ethical Implications of Screening Asymptomatic Indiv

p. 2814. 

44 Mary Ann Baily and Thomas H. Murray, “Ethics, Evidence, and Cost 

born Screening.” 

45 Neil A. Holtzman and Theresa M. Marteau, “Will Genetics Revol

Medicine?” 

46 Robert T. Croyle, Psychosocial Effects of Screening for Disease Prevention and 

(New York: Oxford, 1995). 
pyp

benefit the patient while suppressing the information that is li

lead to net harm. 

One example will suffice to show just how complex and elus

the benefits and harms involved in each component of 

screening. The case of Duchenne muscular dystrophy (DM

been examined with great sensitivity by pediatrician-ethicist 

Friedman Ross, whose review of the case we draw on here.4

born screening for DMD is currently being offered to par

certain hospitals in Ohio as part of a pilot project funded 

CDC.49 DMD is an X-linked degenerative disease of the m

that affects about one in 3,500 boys. Symptoms usually beg

fore the age of six and lead to braces, wheelchair dependenc

death before the age of thirty. There is considerable supp

newborn screening of DMD even though it does not meet th

son-Jungner criteria of having an accepted treatment and an 

policy on whom to treat. DMD is more common than PKU 

natural history is well understood. But, as Ross writes, “th

concern is whether early diagnosis improves prognosis.”50 

One problem is that the standard treatment for DMD with 

costeroids has deleterious side effects and may be inappropri

                                                      

47 James W. Mold and Howard F. Stein, “The Cascade Effect in the Clini

of Patients,” New England Journal of Medicine 314 (1986): 512-514; and Ric

Deyo, “Cascade Effects of Medical Technology,” Annual Review of Public H

(2002): 23-44. 

48 Lainie Friedman Ross, “Screening for Conditions that Do Not Meet 

son and Jungner Criteria: The Case of Duchenne Muscular Dystrophy,” A

Journal of Medical Genetics Part A 140A (2006): 914-922. 

49 See www.cdc.gov/ncbddd/duchenne/screening.htm. CDC is also fu

pilot DMD screening program in Georgia for boys ages six through 

months. 

50 Lainie Friedman Ross, “Screening for Conditions that Do Not Meet 

son and Jungner Criteria: The Case of Duchenne Muscular Dystrophy,” p
ggj

stigmatization, discrimination, and unnecessary psychological 

On the other hand, there are data indicating that early scree

the only effective way to diagnose DMD without considera

lay. 

Some experts argue for DMD screening as a way to assist “

ductive decision-making” and “life planning”; but these 

benefits to the family must be weighed against the potential 

of diagnosing the child months or years before he or she be

symptomatic, harms that include needless anxiety, disruption 

parent-child bond,51 and the possibility that parents will misu

information52 or seek out dangerous alternative treatments,53 

mention the ill effects of false-positives.54 To further complic

                                                      

51 If the diagnosis is made later in life, then a strong bond is allowed 

early, and the parents’ love for the child will lead them to do what is in th

best interest. If the diagnosis is made too early, there is a risk that a parent 

the child from the beginning as a “defective” being and not simply as “my

52 When a child has been identified early as genetically “abnormal,” the 

may be inclined to treat him or her as a second-class member of the 

Nancy Wexler tells of a woman whose two young children were at risk fo

ington’s disease and who wanted to have them tested early because “she o

enough money to send one to Harvard.” See Nancy S. Wexler, “Clairvoya

Caution: Repercussions from the Human Genome Project,” in The Code 

Scientific and Social Issues in the Human Genome Project, eds. Daniel J. Kev

Leroy Hood (Cambridge, Massachusetts: Harvard University Press, 19

211-243. 

53 Elizabeth Campbell and Lainie Friedman Ross, “Parental Attitudes R

Newborn Screening of PKU and DMD,” American Journal of Medical Genet

(2003): 209-214. 

54 Even false-positive newborn screening results (quickly corrected) ha

found, in some cases, to cause lasting harm to the early bonding of par

child. See Elizabeth A. Gurian, et al., “Expanded Newborn Screening 

chemical Disorders: The Effect of a False-Positive Result,” Pediatrics 117 

1915-1921; and Josephine M. Green, et al., “Psychosocial Aspects of 

Screening of Pregnant Women and Newborns: A Systematic Review,

Technology Assessment 8 (2004): 1-109. For the impact of false positives in s
y g y 

explicit consent from the parents. In Wales, where informe

sent is required, as many as ninety-four percent of parents a

the screening at birth. In Germany, on the other hand, whe

untary screening is offered between one and twelve months 

only five percent of parents elect to participate; these differen

parental acceptance of voluntary DMD screening may simply 

the different circumstances in which the screening is offered. 

All in all, it is difficult to judge whether the benefits of ne

screening for DMD outweigh the risks. All we can safely say 

a thorough informed consent process may help parents unde

the advantages and disadvantages and make a more thou

choice for their infant. Yet multiply this example a hundre

thousand fold and it is easy to see just how difficult it would 

ask parents to weigh the benefits and harms of a greatly exp

newborn screening panel. Already, when states are screenin

borns for at most dozens of heritable disorders, it is imprac

to explain to parents the peculiar risks and benefits of screen

each condition. This task would be all the more daunting i

born screening for thousands of genetic markers were to b

widely available. 

                                                                                                          

for particular diseases, see Michael B. Rothenberg and Edward M. Sills

genesis: The PKU Anxiety Syndrome,” Journal of the American Academy 

Psychiatry 7 (1968): 689-692; Audrey Tluczek, et al., “Psychological Im

False-Positive Results When Screening for Cystic Fibrosis,” Pediatric Pu

Supplement 7 (1991): 29-37; and Göran Bodegård, et al., “Psychologic

tions in 102 Families With a Newborn Who Has a Falsely Positive Screen

for Congenital Hypothyroidism,” Acta Paediatrica Scandinavica Supplem

(1983): 2-21. 

55 The authors conclude that, “Concerns about the negative effect of n

screening on the early mother-baby relationship have not been substan

Evelyn P. Parsons, et al., “Newborn Screening for Duchenne Muscular 

phy: A Psychosocial Study,” Archives of Disease in Childhood Fetal and 

Edition 86 (2002): F91–F95. 
pgppy g

it belong to the child alone, to use or to disregard as he or sh

fit once he or she becomes an adult? Or do parents (as so

them seem to believe) have an unlimited right to know the 

abnormalities of their children? Do physicians have a claim o

information once it exists? Should the state in which the c

born, in the interest of building ever more useful genomic 

bases, have a presumptive right to “biobank” the child’s gen

data? If newborn screening detected a range of unfavorable 

positions in the child’s genome, would they amount to “pre-e

conditions” that insurers or even potential employers would 

titled to consult before offering the patient health insura

employment?57

                                                      

56 The question of what should be done with the dried blood specimens 

from newborn screening is resolved differently in different states. Som

store the samples indefinitely; others discard them after a few month

states have policies permitting the use of residual blood spots outside of t

born screening context, for forensic, clinical, evaluative, or epidem

investigations. Very few states inform the parents that their child’s bloo

be retained. When used for such research purposes, the blood samples a

nymized,” but some observers are concerned that they could be re-id

through database linkage or genomic fingerprinting. See Richard S. Olne

“Storage and Use of Residual Dried Blood Spots from State Newborn S

Programs,” Journal of Pediatrics 148 (2006): 618-622. 

57 The fear that genetic information, once gathered, might subject the in

to insurance or employment discrimination led Congress to pass (and P

Bush to sign into law) the Genetic Information Nondiscrimination Act 

of 2008. The Act “prohibits group health plans and health insurers from 

coverage to a healthy individual or charging that person higher premium

solely on a genetic predisposition to developing a disease in the future. T

lation also would bar employers from using individuals’ genetic informatio

making hiring, firing, job placement, or promotion decisions.” See State

Administration Policy, April 25, 2007, online at www.genome.gov/ 

Pages/PolicyEthics/GeneticDiscrimination/SAPonHR493.pdf. Only ti

tell whether GINA will prove successful in preventing insurance and emp

discrimination based on the results of genetic screening and testing. 
g g 

parent (or the state, if the screening is mandatory) to make t

cision on the infant’s behalf, but such a transfer of respon

raises serious ethical questions. The case of Huntington’s dis

instructive here. As noted above, Huntington’s is a late-onse

rological disorder, always fatal, and at present untreatable. 

dominant and fully penetrant Mendelian disorder, which mea

children of a parent who has been diagnosed with Huntin

have a fifty percent chance of having the gene and the 

themselves. The defective gene has been identified, and the

definitive DNA-based test for its presence. Nancy Wexler ha

ten with passion and eloquence on the tremendous comple

the question of whether or not someone at risk for Huntin

should choose to be tested.58 In the end she concludes that t

no right decision for everyone, and that each person at risk m

allowed to make that decision for him or herself after re

young adulthood. Although Huntington’s is far from typ

most genetic disorders, Wexler draws some general concl

above all, that truly informed consent, including a full psycho

appreciation of the ramifications of the information, must 

principle upon which testing programs are designed. Infor

should not be foisted on someone without permission.59

As there is currently no treatment and no medical benefit from 

detection, and a positive diagnosis is so potentially devas

there has been widespread agreement that Huntington’s is 

the genetic disorders least suitable for routine screening, esp

                                                      

58 Nancy S. Wexler, “The Tiresias Complex: Huntington’s Disease As a P

of Testing for Late-Onset Disorders,” FASEB (Federation of American So

Experimental Biology) Journal 6 (1992): 2820-2825. See also Wexler’s pres

before this Council on September 8, 2006, available online at www.bioeth

transcripts/sept06/session6.html. 

59 Nancy S. Wexler, “The Tiresias Complex: Huntington’s Disease As a P

of Testing for Late-Onset Disorders,” p. 2824. 
gppy 

those like Huntington’s that should be left up to the indivi

the other end. Yet it is quite likely that the psychological com

of the personal decision whether to be tested for Huntin

would also be present in the case of other genetic disorders, 

they are not fully penetrant and invariably fatal. Deciding to 

for a multitude of conditions means taking from children th

to decide these questions for themselves when they have reac

age of sufficient maturity and thoughtfulness. Although nom

exercised for the benefit of the child, routine newborn scree

inevitably in some measure a violation of the child’s right “

know,” if that were his or her choice. This may be a price 

paying, but it ought to be paid in full awareness of its meaning

E. Genetic Disease and Human Difference 

There is also a danger that, with genomic medicine and un

genetic profiling, there will be a blurring of the distinction b

genuine disease and mere difference. Only a small proportion 

abnormal gene variants uncovered by newborn profiling w

directly and inexorably to serious illness. Typically, medically 

tant SNPs will merely correlate (often in combination with 

SNPs) with elevated susceptibilities for various medical cond

and even these correlations will be unpredictable and highl

able, depending on a host of unknown factors. The imp

discipline of epigenetics teaches that an individual’s actual 

will be a complex result of genetic and environmental facto

will not be determined simply by his or her genes. 

                                                      

60 See Dena S. Davis, “Genetic Dilemmas and the Child’s Right to an O

ture,” The Hastings Center Report 27 (1997): 7-15. We shall return to the 

informed consent in our discussion of state-mandated newborn scree

Chapter Four. 
g pgy

question whether all this information about the children’s p

medical future will be used for their benefit and will not sh

adverse ways the parents’ view of their children, their wort

their prospects for happiness. Furthermore, what will it be l

children to grow up in possession of this vast storehouse of 

information? Will they see it as an entirely beneficial resource

used throughout life to improve their health, adjust their hab

lifestyle, and assist their physicians when diagnosis proves e

Or will it instead be a burden, weighing them down with a fa

sense of limitations and lost possibilities? 

F. Newborn Screening, Genomic Medicine, and 

 Eugenics 

Advocates of a broadened notion of “benefit” often extol the 

of newborn screening for helping parents make future reprod

decisions (e.g., adoption, egg or sperm donation, IVF and 

amniocentesis and abortion, etc.).61 But this notion of “ben

the family” is not unproblematic. First, if the putative benefit 

family is to be realized by preventing the birth of siblings w

detected genetic defect, then it would make more sense to 

for the defect prenatally, so that the family is not burdene

even one defective child.62 Putting it so callously highlights th

                                                      

61 See, for example, Alexander and van Dyck, “A Vision of the Future o

born Screening,” p. S352.

62 In a response to Alexander and van Dyck, the noted British epidem

Nicholas Wald made the following argument: “Neonatal screening is, in g

poor method of alerting couples to a disorder before the birth of an 

child, because it cannot detect the first affected pregnancy in any family. 

screening would often be more effective, identifying most affected preg

including the first one in any family. The argument that neonatal scre

useful in influencing “prenatal diagnosis and family planning” is more 

ment in favor of prenatal screening than a reason for neonatal screenin
gp 

vance, we would have tried to prevent his or her birth? T

affected child, family planning in this sense means not “limit

incidence of a defective gene” but “preventing the birth 

more kids like me.” Here the laudable goal of reducing th

dence of genetic disease comes into collision with the wish a

obligation to treat every family member as a being with in

and equal worth. Moreover, should the uniform panel of con

be greatly expanded, the propriety of its use for family pl

purposes would become even more questionable. Suppose t

panded screening of an infant reveals not a fatal and inc

disease but instead a host of genetic variants, each of which 

confers elevated risk for some condition or other? Who is to 

what point an uncovered defect becomes serious enough to w

preventing the birth of other children who might carry it? A

point have we crossed the line from legitimate family plann

capricious and morally dubious eugenics? 

Indeed, the expansion of newborn screening, however reason

may be in itself, seems symptomatic of a broader phenome

sort of Faustian imperative driving the search for genetic kno

back to earlier and earlier points along life’s path. Neither PG

amniocentesis is new, but it seems likely that as time goes on 

procedures will come to seem more and more like routine o

for prospective parents. Should the information gleaned from 

tests seem sufficiently “negative,” some parents will be temp

discard the “defective” embryo or abort the “defective” fetu

that choice will no doubt be justified as “good” for someo

the unborn child, for the unimplanted embryo, for the p

themselves, for the future siblings, or for society at large. 

way, the blameless intention to diagnose and treat our chi

                                                                                                          

Nicholas Wald, “Neonatal Screening: Old Dogma or Sound Principle?” (

the editor), Pediatrics 119 (2007): 406-407, p. 406. 
pgg y 

decades and preimplantation genetic diagnosis for the last dec

more. The development and spread of these techniques can 

be attributed to the emergence and proliferation of ne

screening.63 Nor can we say that expanded newborn screen

even full newborn profiling) will necessarily lead to more p

or preimplantation testing or that, with the growing accepta

genomic medicine, parents will be more likely to resort to IV

PGD (or to amniocentesis and selective abortion) to preve

birth of genetically inferior offspring—although there are, 

regard, relevant lessons to be learned from the declining inc

of Down syndrome due to selective abortion.64 Genomic

teach us to accept that all of us are born with an assortment 

ease susceptibilities, that genetic perfection is therefore unatta

and hence that prenatal “weeding out” of undesirable geno

impractical and therefore unnecessary, at least in many ins

Certainly there are today many advocates of expanded ne

screening whose chief concern is with the health and well-be

our born children and who are not advocates of expanded p

screening and selective abortion.65 Nonetheless, it is prudent t

                                                      

63 Moreover, limiting the expansion of newborn screening would not af

existing cases in which parents seek prenatal testing based on their desire 

the birth of another child with a genetic disorder. 

64 See Ralph L. Kramer, et al., “Determinants of Parental Decisions A

Prenatal Diagnosis of Down Syndrome,” American Journal of Medical Genetic

79 (1998): 172-174; and Darrin P. Dixon, “Informed Consent or Instituti

Eugenics? How the Medical Profession Encourages Abortion of Fetus

Down Syndrome,” Issues in Law & Medicine 24 (2008): 3-59. 

65 For example, the Cystic Fibrosis Foundation (www.cff.org) places all 

phasis on newborn screening rather than on prenatal diagnosis. On th

hand, their website does explain that carrier testing is available to expect

ents (or to those who are considering having a child) to “determine if a 

might have a child that may have certain diseases or health care needs, 

cystic fibrosis (CF).” The website continues, “Your decision to be ge

tested to learn if you carry a mutation or mutations of the CF gene may 

cult and is a personal choice. You may wish to talk with your medical or 
py y p

Already, a private company and an academic medical center 

fering to the public a cutting-edge DNA-based procedu

prenatal identification of dozens or even hundreds of gene

normalities while the fetus is gestating.67 The technique, 

“microarray-based comparative genomic hybridization,” or 

CGH” for short, examines the DNA of the fetus for minut

tions and insertions that have been linked to disea

deformities.68 The private company, Signature Genomic Lab

ries of Spokane, Washington, charges $1,850 for the use 

“Signature PrenatalChip,” and already (as of November 200

mothers have had their physicians send in DNA samples from 

fetuses so that they could be analyzed for the presence of 

than seventy genetic syndromes associated with mental retar

                                                                                                          

advisors to help you decide. The American College of Obstetricians an

cologists (ACOG) suggests that all couples who are considering having a 

or those who are already pregnant—should have genetic carrier testing fo

 For its part, the ACOG website explains, “The purpose of having 

formation about your developing baby is so you can prepare yourself to c

child with special health care needs or so you can terminate the pregnanc

www.acog.org/from_home/wellness/cf001.htm.) 

66 Again, this is not to suggest that the expansion of newborn screening sh

held responsible for any future increase in the use of prenatal and preim

tion testing. The availability of less invasive testing methods, such as blo

for pregnant women, will be a more likely cause of significant growth in t

tice of prenatal testing. See Ainsley J. Newson, “Ethical Aspects Arisin

Non-Invasive Fetal Diagnosis,” Seminars in Fetal and Neonatal Medicine 13 

103-108. 

67 See Bridget M. Kuehn, “Prenatal Genome Testing Sparks Debate,” Jour

American Medical Association 300 (2008): 1637-1639. 

68 See Trilochan Satoo, et al., “Prenatal Diagnosis of Chromosomal Abno

Using Array-Based Comparative Genomic Hybridization,” Genetics in M

(2006): 719-727; Lisa G. Shaffer, et al., “Comparison of Microarray-Based 

tion Rates for Cytogenetic Abnormalities in Prenatal and Neonatal Spec

Prenatal Diagnosis 28 (2008): 789-795; and Catherine D. Kashork, et al., “

Diagnosis Using Array CGH,” Methods in Molecular Biology 444 (2008): 59-7
y y g pg

array CGH in 4,000 pregnancies.70 Should that study be dee

success, multiplex prenatal screening might soon become a 

monplace practice. 

It is not at all clear what parents are supposed to do with the 

mation gleaned from such prenatal testing, especially 

identified abnormalities are of questionable or variable clinic

nificance, as many of them certainly will be. Some coupl

presumably consider terminating the pregnancy if the res

DNA testing are sufficiently “bad” (otherwise why pay for s

expensive procedure?). But how bad does the news have to 

tempt the parents to prevent the birth of a “defective” child

stantial numbers of parents are prepared to terminate a pregn

the chromosomal abnormality that causes Down syndrome 

vealed by amniocentesis. But what will they do when platform

the Signature PrenatalChip reveal that their baby might suffe

such varied conditions as Marfan syndrome (a disorder of th

nective tissue believed by some physicians to have a

Abraham Lincoln), brachydactyly (causing shortness of the 

and toes), nail-patella syndrome (which may cause poorly dev

nails and other deformities), or X-linked short stature (af

only boys)? What are parents to do when told—as the Sig

chip can tell them—that their unborn child has certain DNA 

tions believed to confer a slightly elevated risk of schizoph

How such information will be used, and whether gathering 

truly be said to benefit the child who undergoes testing, are 

                                                      

69 Kuehn, “Prenatal Genome Testing Sparks Debate,” p. 1637; Rob Stein

Hopes and Concerns as Fetal DNA Tests Advance,” The Washington Post, 

26, 2008. Signature Genomics Laboratories (www.signaturegenomics.com

talchip.html) assures potential users of its PrenatalChip that, when scan

fetus’ DNA, “specific loci have been excluded which are associated wit

onset conditions.” 

70 Rob Stein, “Fresh Hopes and Concerns as Fetal DNA Tests Advance.” 
g y p

baby’s birth. 

G. Genetic Information and the Problem of SelfKnowledge 

We presented in the preceding part of this chapter the arg

that, with newborn profiling, a sense that everyone has his 

own share of genetic imperfections and that “we are all in t

gether” might soften the impact of any bad news. The psych

burdens, to children as well as to parents, of living with an 

fied genetic abnormality, would certainly be more widely 

every couple were to go home from the hospital with a virtu

lanche of information about the genetic defects and suscept

of their newborn child. But we then would be in uncharted 

tory, and it is not at all clear how human beings would ad

such a massive increase in genetic self-knowledge. More pr

we are speaking here of a massive increase of self-information, 

does not automatically translate into wisdom or genuin

knowledge. 

Such reflections lead, finally, to the deeper and more tro

question of the value of knowledge itself for human happin

Nancy Wexler wrote, 

The blind seer Tiresias confronted Oedipus with the qui

tessential dilemma of modern genetics: “It is but sorrow 

be wise when wisdom profits not.”71

                                                      

71 Nancy S. Wexler, “The Tiresias Complex: Huntington’s Disease As a P

of Testing for Late-Onset Disorders,” p. 2820, quoting Sophocles, Oedipu

nos, lines 316-317. 
gy 

there that, used wisely, will improve our lives and help free u

illness, infirmity, and uncertainty. Yet there is also the pos

that such knowledge will be misused or misinterpreted, that 

tempt us to stigmatize and to discriminate against the gen

unfortunate, and that under its weight some of us will incl

ward fatalism and despair. 

IV. On the Necessity and the Limits of Speculation 

In the preceding two sections, we have sought to describe 

sential elements of the cases for and against newborn profilin

have marshaled arguments suggesting that the logic of perso

medicine and of technological progress will, in time, yie

equivocal benefits for infants and their parents, for pediat

and biomedical scientists, and for society at large. But we ha

assembled reasons to doubt whether the convergence of ge

medicine and newborn screening will be either as impressive 

timately as desirable as some of its proponents may believ

have sought to tether these prognoses to certain known facts 

the present: for example, to the plummeting cost of whole-g

sequencing; to the growing number of companies offering 

able gene chips and other DNA-based screening platfor

surveys that have revealed keen parental interest in genetic in

tion about offspring; and to the impact of amniocentesis 

declining incidence of children born with Down syndrome. 

theless, our analysis of the case for and the case against ne

profiling has been an exercise in speculation—one that is bot

essary to attempt but also limited in its usefulness for purpo

ethical analysis and policymaking. It is limited insofar as th

definitive test of our prognoses—about both the benefits a

harms of newborn profiling—will be the day to day unfold

this imagined future. But such speculation is also necessary 

ethical analysis and policymaking are to be well informed a
gpy

think imaginatively about what the convergence of newborn s

ing and genomic medicine will bring, we may find ou

overtaken by a future for which we are ill-prepared. Rathe

approach the future blindly, we should—bearing in mind th

ited range and sharpness of our prospective vision—o

awareness and transparency. 

Our concern for awareness and transparency has only been 

ened by the ACMG report and its aftermath, for it appears t

implications of the report’s recommendations—amounting 

fundamental change in the moral focus of newborn scree

were certainly not brought out in transparent ways for the pu

of public discussion and optimally informed policymaking. T

both the federal and the state levels, we are confronted w

question: What should we do now? 

\[
85

NEWBORN SCREENING: 

MANDATORY, ELECTIVE, OR BOT

aving explored, in Chapter Three, some of the eth

sues that are likely to emerge more fully in future d

as newborn screening evolves under the aegis of ge

medicine, we return, in this final chapter, to the present s

newborn screening, and specifically to an ethical dilemma th

confronts us with some urgency as the states continue to e

their newborn screening programs. We have sought to clarify

to imagine—both the potential benefits and the potential ha

newborn screening, which are so intertwined that it will be di

in newborn screening policymaking, to avoid the latter while 

ing the former. The prudent course, in our opinion, is to re

that the primary goal of newborn screening is to provide 

medical benefit to children affected by serious disease, an

mandatory newborn screening can be justified only when t

convincing evidence that the benefits for the infant of scr

and treatment outweigh the risks and burdens. For conditio

do not meet this standard of evidence, screening may proce

it should not be mandatory; instead, it should be offered to p

as a pilot program within a research paradigm, and it should 

their voluntary, informed consent. 

Our challenge in this chapter is to defend this recommen

With this aim in mind, we begin, in the first part, with a disc

of two opposing approaches to newborn screening. One cham

mandatory screening for both conditions that are treatab

those that are untreatable. This is the approach advocated 

ACMG in its 2005 report. The other approach insists that a

H
ppp

In the fourth part, we conclude with a detailed recommen

that provides an ethically sound framework for public po

newborn screening. 

I. Mandatory Screening Versus Informed Parental Con

The question of whether or to what degree newborn scr

should be mandatory has excited controversy ever since 

screening began in the 1960s.1

 The paradigmatic justificati

mandatory screening for a health condition is that the condi

undetected and uncontrolled, would pose a threat to the he

others in the community (as is especially the case with certain 

contagious diseases). In the absence of such a threat, gover

coercion seems harder to justify, and screening of children is 

taken to require the parent’s voluntary, informed consent.2

 N

                                                      

1 See Beth A. Tarini, et al., “Waiving Informed Consent in Newborn S

Research: Balancing Social Value and Respect,” American Journal of Medica

Part C (Seminars in Medical Genetics) 148C (2008): 23-30. 

2 The report that Wilson and Jungner prepared for the World Health O

tion in 1968 says little on the question of mandatory versus voluntary sc

But in their 2003 Review of Ethical Issues in Medical Genetics, also commissi

the World Health Organization, Dorothy C. Wertz, John C. Fletcher, a

Berg argue that genetic screening in general ought to be voluntary and to 

informed consent, except screening of newborns, which ought to be mandatory 

only if early diagnosis and treatment would benefit the newborn.” Here 

cerpts from their argument (on pp. 39-40 of the Review), which will pro

pertinent to our analysis of the ACMG report’s recommendations: 

Societies have an ethical obligation to protect their most vulnerab

members, especially if these people cannot protect themselves. Ne

borns deserve the special protection afforded by mandatory screeni

for disorders where early diagnosis and treatment favourably aff

outcome. In arguing for inclusion of a disorder on the list of mand

tory screens, public health authorities should be able to prove th

early diagnosis and medical treatment make a difference for the pop
rationale for making PKU screening compulsory was chiefly t

the face of reluctance by the medical establishment to em

screening and dietary treatment for PKU, legal mandates w

only practical way to ensure that most children would be 

Failure to identify affected children and start them promptl

restricted diet could lead to irreversible neurological damage 

a few weeks of birth. The momentum to enact state laws man

PKU screening was reinforced by the lobbying efforts o

chapters of the National Association for Retarded C

(NARC), by the powerful support of President Kennedy, and 

tireless advocacy of Robert Guthrie himself, described here 

own words: 

                                                                                                          

lation of newborns with the disorder. The psychosocial benefits 

simply having a diagnosis, in the absence of treatment, are not suf

cient to justify mandatory screening... 

 The primary purpose of mandatory newborn screening is to ben

fit the newborn through early treatment. Some treatments (e.g., f

PKU) must be instituted immediately in order to be effective. It mak

no sense to provide screening if timely treatment is not available... 

 The introduction of multiplex screens such as tandem mass spe

troscopy raises new ethical issues, because it may lead to t

identification of diseases that are not treatable at the present tim

There are both benefits and risks associated with knowing that an a

parently healthy newborn will develop one of these diseases early 

life. For some parents, the knowledge may lessen self-blame and p

vent weeks or months of searching for a diagnosis. Paren

knowledge may also confer a benefit to the child, because paren

could be prepared to take advantage of new and rapidly-evolvi

treatment. So, on the other hand, some parents may not wish to kno

preferring to enjoy the months or years before symptoms appear. O

balance, it appears that the benefits of parental knowledge outwei

the risks. However, parents who do not wish to know about curren

untreatable disorders should have the opportunity to “opt-out” fro

receiving this information... 
py 

including lay groups such as the National Association f

Retarded Children and physicians. The most positive r

sponses came from non-physicians.3

Massachusetts became the first state to make PKU screening 

pulsory in 1963; by 1975, forty-three states had enacted suc

and ninety percent of all newborns were being tested.4 Toda

born screening is mandated in forty-eight states.5 However, 

four of the states (Michigan, Montana, Nebraska, and Sou

kota) permit parents to opt out of newborn screening for re

reasons, and some states allow parents to opt out for any r

                                                      

3 Robert Guthrie, “The Origin of Newborn Screening,” Screening 1 (1992): 

11. Of this period, historian of medical genetics Diane Paul writes, “M

screening was opposed by the American Medical Association and ma

medical societies. More surprisingly, compulsory screening was also o

rather quietly by many researchers in the field of human metabolism. Fo

ety of reasons, these researchers believed it premature to mandate th

infant be tested for PKU and their reservations intensified during the f

years of the screening programs.” Diane B. Paul, “The History of N

Phenylketonuria Screening in the U.S.,” Appendix 5 of Neil A. Holtzm

Michael S. Watson, Promoting Safe and Effective Genetic Testing in the Unite

Final Report of the Task Force on Genetic Testing (Bethesda, Maryland: Nation

tutes of Health, 1997), available online at biotech.law.lsu.edu/research/fed

appendix5.htm. 

4 Diane B. Paul, “The History of Newborn Phenylketonuria Screenin

U.S.” 

5 One state (Massachusetts) mandates screening for certain conditions w

fering optional screening (requiring informed parental consent) fo

conditions. The Massachusetts model of newborn screening is discussed 

in the next section. 

6 See Bradford L. Therrell, et al., “Status of Newborn Screening Pro

S212-S252, Appendix 2, “Information From Statutes and Regulations o

Genetic Privacy and Newborn Screening,” pp. S226-S228; see also E

Hiller, et al., “Public Participation in Medical Policy Making and the S

Consumer Autonomy: The Example of Newborn Screening Program

United States,” American Journal of Public Health (1997): 1280-1288. 
pgy gp

who are determined to refuse such screening are able to do 

most everywhere in the United States.9

In Maryland, Wyoming, and the District of Columbia, ne

screening explicitly requires informed parental consent.10 In g

                                                      

7 Personal communication, November, 2008, from Susan R. Panny, MD

tor, Office for Genetics and Children with Special Health Care 

(OGCSHCN), Maryland Department of Health and Human Hygiene. In 

these high compliance rates, the number of babies who are born with 

diseases that go undetected because of parental refusal of newborn scre

likely to be very small. According to Dr. Panny, an informal survey of th

in 2007 turned up only nine known “missed cases” due to parental refus

of them dating to the early 1990s. 

8 For example, Kathryn Fant and colleagues found that, among forty-tw

that grant parents the option to refuse newborn screening, only twen

(fifty-five percent) mention that option in the educational materials they 

parents prior to drawing the infant’s blood. See Kathryn Fant, et al., “Co

ness and Complexity of Information Available to Parents from N

Screening Programs,” p. 1270. 

9 Of the four states whose laws do not explicitly permit parents to op

newborn screening, only Nebraska has a legal enforcement provision, an

chosen to exercise it only once: in 2007, a baby born to parents who obj

the drawing of blood on religious grounds was seized by sheriff’s deputie

the heel-stick blood test could be administered. See Anna Jo Bratton, “

Says Seizure of Baby for Test Violated Rights,” The Associated Press, Oct

2007. On December 5, 2008, the Nebraska Supreme Court ruled that th

mandatory newborn screening law does not violate the parents’ right to 

freedom; however, the court also concluded that, in the 2007 case, the s

not proved parental neglect and should not have seized the baby. See In r

of Joel Anaya, A Child Under 18 Years of Age. No. S-07-1136, filed Dece

2008. 276 Neb. 825; available online at www.supremecourt.ne.gov/opinio

2008/december/dec5/s07-1136.pdf. 

10 In Maryland, parental informed consent for newborn screening is req

regulation (not by statute). Title 10, Department of Health and Mental H

Regulation No. 10.52.12.05, reads, in part: “Before administration of the 

parent or guardian shall be informed fully of the reasons for the test and o

her legal right to refuse to have the test performed on the child. An in
pgg 

read and asked to sign a consent form, or given a brochu

asked if they would like to sign an “opt-out” form. Evidentl

ents are very likely to accept newborn screening if they are a

by their doctors that it is a good idea. This is not surprising: 

of the number and the obscurity of the targeted conditions, a

complex balance of risks and benefits involved in each scr

decision, it is unrealistic to expect parents to attain su

knowledge to make an informed decision about the conditio

which their children should be screened.12

                                                                                                          

who has been provided and has signed a written explanation of the test a

and furnished by the Department shall be considered fully informed.” (a

online at www.dsd.state.md.us/comar/10/10.52.12.05.htm.) In Wyoming 

District of Columbia, parental consent is required by statute: Wyoming 

§35-4-801, under Title 35, Public Health and Safety, reads, in part: “In

consent of parents shall be obtained and if any parent or guardian of a c

jects to a mandatory examination the child is exempt from [newborn scre

(available online at legisweb.state.wy.us/statutes/dlstatutes.htm.) For the 

of Columbia, D.C. Code Annotated §7-834 reads, in part: “Participation 

sons in metabolic disorder programs in the District of Columbia sh

wholly voluntary, and...the Mayor shall further insure that: (A) No test 

formed on any newborn over the objections of his or her parent and tha

be performed unless such parent is fully informed of the purpose of tes

metabolic disorders, and is given a reasonable opportunity to object to su

ing; (B) No program requires mandatory participation...” (available o

www.lawsource.com/also/usa.cgi?xdc). 

11 For example: In Maryland, in recent years, five or fewer families have w

their consent for newborn screening, out of approximately 75,000 bab

each year. These numbers are comparable to the numbers of parents who 

of “mandatory” newborn screening in Indiana, Missouri, New York, an

states. (Susan R. Panny, personal communication.) In Wyoming, in 20

families refused newborn screening, out of approximately 6,800 babies 

the state. (Dena Freeman, “Informed Consent and Newborn Screening

Practicum, 2008, Institute for Public Health Genetics, University of Was

available online at sphcm.washington.edu/practicum/Dena%20Freeman.p

12 On doubts about the attainability of “genuine informed consent,” see 

Schneider, “Some Realism About Informed Consent,” Journal of Labora

Clinical Medicine 145 (2005): 289-291; and C. H. Braddock, III, et al., “In
pgg

report, the Committee on Assessing Genetic Risks of the In

of Medicine (IOM) stated that “mandatory screening has no

shown to be essential to achieve maximum public health be

however, it is appropriate to mandate the offering of establishe

(e.g., PKU and CH) where early diagnosis leads to improved 

able outcomes.”14 In 2001, the Committee on Bioethics 

American Academy of Pediatrics (AAP) issued a report favor

introduction of an informed consent process for newborn s

ing, in part because it would “promote more tho

understanding of the implications of the tests.”15 

In support of the informed consent approach, some critics o

datory newborn screening have raised doubts as to w

decision-making regarding screening should follow a public 

model (e.g., for contagious diseases) as distinguished from a 

model (i.e., where only the good of the individual patient is in 

tion). For example, in 1982, George Annas, an expert in hea

and bioethics, wrote a brief on behalf of parental liberty and 

governmental effectiveness, i.e., in favor of voluntary inf

consent and against mandatory screening, even in the cas

highly successful newborn screening program such as PKU s

ing.16 A study by bioethicist Ruth Faden and her colleagues h

shown that, in the state of Maryland, “requiring informed c

                                                                                                          

Decision Making in Outpatient Practice: Time to Get Back to Basics,” J

the American Medical Association 282 (1999): 2313-2320. 

13 National Research Council, Genetic Screening Programs, Principles, and Resear

14 Committee on Assessing Genetic Risks, Institute of Medicine, Assessin

Risks: Implications for Health and Social Policy, Lori B. Andrews, Jane E. F

Neil A. Holtzman, and Arno G. Motulsky, eds. (Washington, D.C.: N

Academies Press, 1994); emphasis in original.

15 Committee on Bioethics, American Academy of Pediatrics, “Ethica

With Genetic Testing in Pediatrics,” Pediatrics 107 (2001): 1451-1455. 

16 George J. Annas, “Mandatory PKU Screening: The Other Side of the 

Glass,” American Journal of Public Health 72 (1982): 1401-1403. 
g py 

screening.18 Against such arguments, Annas made the case th

few parents who refuse newborn screening are, in fact “mora

tified in their refusal,” in part because the high rate of false po

poses health risks that may not be trivial.19 Annas gave the f

ing argument: 

This may not strike one as an adequate reason for refusin

PKU screening. But look into the future when we will 

able to screen for 1,000 more diseases. Suppose, for e

ample, a computerized screening test for 1,000 condition

Suppose further that each of these tests has been so pe

fected that the false positive rate is only 1 percent. Ea

infant screened will then be diagnosed initially as sufferin

from 10 disorders, even though he/she suffers from non

If the false positive rate is 5 percent per test, he/she w

appear to have 50 disorders, etc. The [more] tests that a

performed for rare diseases, the more likely it is that p

thology will be generated from the retesting procedure

and the more rational a decision not to screen initially b

comes. This is independent of any stigma that m

accompany a true positive diagnosis. The rare parent wh

                                                      

17 George J. Annas, “Mandatory PKU Screening: The Other Side of the 

Glass,” p. 1401. The Maryland survey is, Ruth Faden, A. Judith Chwalow

Holtzman, and Susan D. Horn, “A Survey to Evaluate Parental Consent a

Policy for Neonatal Screening,” American Journal of Public Health 72 (1982

1352. Faden and colleagues found that, in Maryland, only five out every 

mothers declined newborn screening. They also found that slightly mo

half the mothers preferred to have their permission sought for newborn 

ing. 

18 The commentary is, Ruth Faden, Neil A. Holtzman, and A. Judith C

“Parental Rights, Child Welfare, and Public Health: The Case of PKU 

ing,” American Journal of Public Health 72 (1982): 1396-1400. 

19 George J. Annas, “Mandatory PKU Screening: The Other Side of the 

Glass,” p. 1401. 
gppy 

the medical model, with its emphasis on the good of t

individual patient, is more appropriate.20

In their commentary, Faden and colleagues had emphasize

they were questioning informed consent only for PKU (and f

other condition where the benefits of newborn screening 

outweigh the harms). When the benefits and risks of screenin

condition are less clear, they wrote, 

[I]t may be necessary to inform parents that certain scree

ing tests are optional while others are not. Before a poli

of compulsory neonatal screening is adopted, each cond

tion for which screening is contemplated must 

considered individually against harm principle consider

tions, the role of parental expertise, the value of fam

privacy, and other factors.21

In this passage, Faden and her colleagues appear to be calling 

alternative approach to newborn screening that recognizes th

some conditions, screening is appropriately mandatory; for 

screening should be elective and voluntary, at least until the 

tion is better understood and an effective treatment is develop

II. A Two-Tiered Approach to Newborn Screening 

The approach that emerges from the ethical analysis of Fad

her colleagues is by no means merely hypothetical; it is wh

state of Massachusetts has been practicing for almost a deca

                                                      

20 Ibid., pp. 1402-1403.

21 Ruth Faden, Neil A. Holtzman, and A. Judith Chwalow, “Parental 

Child Welfare, and Public Health: The Case of PKU Screening.” 
for a “routine” panel of ten conditions, unless parents object 

basis of religious beliefs.22 Parents are also offered “optional

born screening for an additional twenty disorders.23 The o

screening is presented to the public in the form of two “pilo

grams” (one for cystic fibrosis, the other for ninetee

metabolic disorders), i.e., “research studies” whose purposes 

following: 

1. To evaluate the benefit of newborn screening in 

bringing babies with possibly serious medical conditions to early medical attention. 

2. To find out how often these disorders occur in Massachusetts. 

3. To evaluate the laboratory tests used to screen for 

these disorders.24

In explaining the distinction between routine and optional s

ing, Kathleen Atkinson and colleagues at the Massac

Newborn Screening Advisory Committee wrote about th

metabolic disorders on the optional panel as follows: 

                                                      

22 See the brochure “Answers to Common Questions About Newborn 

ing” of the Massachusetts Newborn Screening Program, on

www.umassmed.edu/uploadedfiles/nbs_eng.pdf. The ten actually includ

of the ACMG’s core conditions, plus the infectious disease congenital to

mosis. (Three of the ACMG report’s hemoglobinopathies are cou

Massachusetts as one.) 

23 Kathleen Atkinson, et al., “A Public Health Response to Emerging T

ogy: Expansion of the Massachusetts Newborn Screening Program,” Publ

Reports 116 (2001): 122-131. The twenty include CF (an ACMG core co

plus nineteen metabolic disorders detectable by MS/MS, some of them i

in the ACMG core panel, others in the secondary panel. 

24 “Answers to Common Questions About Newborn Screening” of the 

chusetts Newborn Screening Program. 
formation, as yet unavailable, on the epidemiology, ran

of symptoms, natural history, and treatment of these d

orders. Some children identified with biochemic

abnormalities at birth might later have no clinical pro

lems (overdiagnosis bias); nonetheless, these childr

might be considered ill by their parents throughout chil

hood, and they might also have difficulty obtaining heal

insurance.25

Although the pilot programs are primarily research-oriented

kinson and colleagues reported that, by the fall of 

“approximately 97% of parents had participated in the inv

tional screening.”27 Thus, their experience suggests that a vol

informed consent process, in a screening program offered 

public as an experimental “pilot study,” does not necessarily 

low parental compliance with newborn screening. 

It is important to emphasize that this high rate of parental c

ance even with pilot screening does not mean that an inf

consent process is effectively useless. We noted earlier that it 

realistic to expect parents to attain a sophisticated knowledge 

multitude of obscure genetic conditions for which babies ar

screened. The vast majority of parents seem to accept the m

establishment’s judgment that such screening is beneficial fo

children. But in the context of a two-tiered screening system

as that of Massachusetts, an informed consent process is, pot

at least, of considerable value in educating the parents. The

                                                      

25 K. Atkinson, et al., “A Public Health Response to Emerging Technolo

pansion of the Massachusetts Newborn Screening Program,” p. 126. 

26 Most Committee members agreed that “a population-based study of ne

for CF and metabolic disorders was indeed research on human subjects.” 

126. 

27 Ibid., pp. 127-128. 
y p

the target of voluntary research studies. Moreover, however 

tant this distinction may be in the present era of MS/MS, 

become all the more critical in the future, as we turn to mul

DNA-based genetic screening, with its potential to reveal tho

or tens of thousands of genetic abnormalities of uncertain 

significance. In a two-tiered approach to newborn screenin

great value of the informed consent requirement is that it e

ages parents to keep firmly in mind the ethical difference b

screening their children for well-understood, treatable diseas

enrolling them in medical research projects of uncertain ris

benefits. A clear public grasp of this distinction will prove to 

tally important as the line between therapeutic and re

screening is increasingly blurred by the progress of genomic s

ing methods. 

In addition to requiring explicit parental consent, the Massach

pilot screening programs were initiated only after winning ap

from Institutional Review Boards (IRBs) at both the Massach

Department of Public Health and the University of Massachu

                                                      

28 Atkinson and colleagues write that, “According to federal regulations, 

proval is needed for all ‘research involving human subjects,’ with research 

as ‘a systematic investigation (that is, the gathering and analysis of infor

designed to develop or contribute to generalizable knowledge.’” (Ibid., 

However, federal regulations require IRB approval for research involving 

subjects only if the research is “conducted, supported, or otherwise su

regulation by [a] federal department or agency.” See Office for Protectio

Research Risks, Institutional Review Board (IRB) Guidebook (Washington, D

tional Institutes of Health, 1993), available online at www.hhs.gov/ohrp/i

guidebook.htm. 

The idea that research involving human subjects requires externa

oversight and approval has a distinguished history dating back to the la

teenth century. As early as 1865, the great French physiologist Claude 

wrote, “The principle of medical and surgical morality...consists in ne

forming on man an experiment which might be harmful to him to any 

even though the result might be highly advantageous to science, i.e., to th
py g 

system, to determine whether, based on additional infor

gathered since 1998, any additional disorders warranted inclu

the mandatory screening panel, and whether any other dis

should be added to the pilot studies. 

B. The Future of Screening in Massachusetts 

As of November 2008, Massachusetts is considering amend

to its regulations governing newborn screening that will con

bly expand the number of conditions on its mandatory scr

panel. In recommending this expansion, the Massachusetts 

born Screening Advisory Committee reaffirmed its commitm

a two-tiered approach to newborn screening and its convictio

the original criteria for mandatory screening remain sound. O

basis of information gathered from the first decade of it

screening program, however, the Advisory Committee conclu

July 2008, that CF should be removed from pilot status and 

to the mandatory screening panel, along with twelve of the ni

                                                                                                          

of others.” (Claude Bernard, Introduction to the Study of Experimental Medicin

C. Greene, trans. (New York: Dover, 1957), p. 101.) In this country, the n

IRB approval of federally-funded human subjects research was establish

memorandum issued by the Research Grants Division of the United State

Health Service (USPHS) in 1966. Such research would thereafter requi

institutional review to “assure an independent determination: (1) of the rig

welfare of the individual or individuals involved, (2) of the appropriatenes

methods used to secure informed consent, and (3) of the risks and p

medical benefits of the investigation.” (U.S. Public Health Service, Div

Research Grants, Policy and Procedure Order #129, “Clinical Investigati

ing Human Subjects,” February 8, 1966.) The USPHS memo was 

response to an influential article by Harvard anesthesiologist Henry K. B

exposing twenty-two examples of ethically questionable medical resear

human subjects. (Henry K. Beecher, “Ethics and Clinical Research,” New 

Journal of Medicine 274 [1966]: 1354-1360.) 

29 K. Atkinson, et al., “A Public Health Response to Emerging Technolo

pansion of the Massachusetts Newborn Screening Program,” p. 129. 
y y

the first time, the regulations should make explicit that som

conditions that do not merit either mandatory or pilot screeni

nonetheless be identified in the course of screening for mand

pilot conditions. The Committee said that such “by-product 

tions,” if found, will be “reported to the attending physici

infants would be followed (like the practice for pilot disorders

If it amends its regulations as proposed, Massachusetts will, i

ruary 2009, begin mandatory screening of all newborns for 

conditions (plus twenty-three by-product conditions), while o

optional screening for six other conditions (and three by-p

conditions). It should be emphasized that all twenty of th

candidate conditions for mandatory screening have been p

pilot screening studies in Massachusetts for close to a decad

dently, during that time, sufficient evidence was gathered fro

pilot programs for the Advisory Committee to conclude tha

of those twenty conditions was now well understood, that an 

tive treatment was available, and that the positive bene

screening and treatment outweighed the risks and burdens. 

Whether these twenty new candidate conditions truly meet t

orous Massachusetts criteria for mandatory screening is p

open to question. For example, at the top of the list is th

amino acid defect ARG, a “urea cycle” disorder that can caus

                                                      

30 See Draft Regulations of July 18, 2008, Department of Public Hea

CMR 270.000: Blood Screening of Newborns for Treatable Diseases and 

ders, available online at www.mass.gov/Eeohhs2/docs/dph/legal/newbo

screen_reg.doc. See also Memorandum of August 13, 2008, Re: Inform

Briefing on Proposed Amendments to 105 CMR 270.000: Regulations Go

Testing of Newborns for Treatable Disease, available online at www.mass

Eeohhs2/docs/dph/legal/newborn_screen_reg.doc. We shall address, 

next section, the ethical question of whether and how states should repo

tive results for these “by-product” conditions. 
y gy y 

ment is poorly understood.”33 In fact, ARG scored so low 

ACMG’s initial survey that it was judged “not appropriate fo

born screening” and was then added to their secondary pan

because it was detectable by MS/MS when used in “full 

mode.”34 On the basis of a small number of case studies, a

some experts believe presymptomatic diagnosis and treatmen

sufficient benefit to justify newborn screening.35 But with AR

not entirely clear (as it is with PKU, for example) that new

who test positive for the disease should be started on a res

diet before symptoms emerge later in childhood. All in all, b

of our limited experience with and understanding of this dise

natural history, and its treatment, it may be premature to clai

it is sufficiently well understood and treatable to warrant man

screening.36

                                                      

31 Eric A. Crombez and Stephen D. Cederbaum, “Hyperargininemia Due 

Arginase Deficiency,” Molecular Genetics and Metabolism 84 (2005): 243-251

thirty cases have been reported in the literature worldwide. (Ibid., p. 24

incidence of ARG is unknown, but is estimated at one in 360,000 births. (

Newborn Screening, p. 193.) 

32 Eric A. Crombez and Stephen D. Cederbaum, “Hyperargininemia Due 

Arginase Deficiency,” p. 250. 

33 ACMG, Newborn Screening, p. 193. 

34 Ibid., p. 64. 

35 Crombez and Cederbaum, “Hyperargininemia Due to Liver Arginas

ciency,” p. 249. 

36 Similar questions could be raised about the Massachusetts Advisory C

tee’s proposal to initiate mandatory screening for two related urea cycle d

carbamylphosphate synthetase deficiency (CPS) and ornithine transcarb

deficiency (OTC). Both of these conditions were deemed by the ACM

unsuitable for newborn screening on the grounds that “natural histo

treatment is poorly understood” and that the conditions cannot be con

detected by MS/MS. (ACMG, Newborn Screening, pp. 201-202, 213-214.) F

of these conditions, the ACMG report concludes, “There is no objec

dence at this time in support of the availability of a screening test.” (Ib

202, 214.) If Massachusetts adopts the amended regulations, it may be 

state in the nation that will screen newborns for OTC. 
has been preserved: conditions are to be moved into the man

screening panel only after studies have shown that their natu

tories are sufficiently well understood and that effic

treatments are available whose positive benefits clearly outwe

risks and burdens of screening and treatment. The Massac

approach to newborn screening therefore remains a viable 

for other states to follow as they expand their screening panel

III. Combining the ACMG’s Recommended Panel and a 

 Two-Tiered Approach 

If the two-tiered model of “routine plus optional newborn s

ing” were to be recommended for every state to follow, that 

of course, entail some revision of the ACMG report’s recomm

tions. It would have to be made clear that only those con

that satisfy the classical Wilson-Jungner screening criteria—

onset conditions that gravely threaten the health of the chil

are well understood in their natural histories, and that can be 

tively treated by timely intervention—should be recommen

the states for inclusion in a mandatory screening panel. All 

conditions—those illnesses whose health risks and natural hi

are poorly understood and for which effective treatments a

yet clearly available—should be presented forthrightly as can

for inclusion in pilot research studies, with optional participat

parents of newborns. Thus, in place of the ACMG’s core an

ondary panels, a revised recommendation would offer to the 

a mandatory screening panel and a list of other conditions d

suitable for optional pilot studies. 

A Newborn Screening Advisory Committee in each state 

then have to determine which of the ACMG’s recommended 

tions belong in the routine panel and which conditions sho

included in pilot screening programs in that state. The Ad
In the interest of uniformity and equity, it would be entirely app

ate to encourage all the states to adopt one and the same man

screening panel, assuming that all the conditions included in 

genuinely worthy of state-mandated newborn screening

ACMG could help the states reach a consensus by recomm

for mandatory screening only those conditions that rigorousl

the classical Wilson-Jungner criteria, while relegating other 

doubtful conditions to the list of disorders that require furt

search and are, therefore, suitable for pilot study. In trying to 

uniformity to the mandatory screening panels, the states them

                                                      

37 Statewide IRB oversight can be arranged in a variety of ways. In Massac

for example, the pilot newborn screening programs require approval from 

boards at both the state Department of Public Health and the University 

sachusetts Medical School. Kenneth Pass and colleagues have describ

these two IRBs shaped the Massachusetts pilot screening programs: 

Two independent human subjects review boards (one representing 

MA Department of Health and one from UMassMed) determined tha

formed consent was necessary. The same two review boards recogn

the presumed benefit and the operational impracticalities of conventi

methods for requesting informed consent; they approved an altern

form of informed consent, i.e., verbal informed consent. Briefly, ve

informed consent requires 

 that educational materials be provided to parents in the form o

brochure 

 that parents be told (optimally in the prenatal period, at minimu

after birth) of the optional research program 

 that parents be asked whether or not they consent to the option

research testing 

 that the only written documentation required would be th

needed to indicate to the testing laboratory when a parent refus

consent. 

See Kenneth Pass, et al., “Pilot Programs in Newborn Screening,” Mental 

tion and Developmental Disabilities Research Reviews 12 (2006): 293-300, p. 296. 
y gg p

diverse pilot screening programs under a research paradig

country can reap the benefits of federalism; i.e., the fifty stat

serve as fifty laboratories in which to study the costs and ben

screening for a multitude of conditions whose clinical signi

and appropriate treatment are still in doubt. If all babies born 

United States are uniformly screened for exactly the same 

tions, it becomes very difficult to study the overall effic

screening versus not screening for a particular disorder. It is 

advantage of our federal system that states can learn from 

other what works best, adopting the successful models and d

ing the failed ones. 

One foreseeable problem with a two-tiered approach co

those conditions that are necessarily identified as part of the 

ential diagnosis of the mandated conditions (referred to 

white paper as “incidental findings” or “by-product condit

Some would argue that any clinically significant results must 

ported to the child’s physician and parents, even if those 

were obtained inadvertently in the course of testing for other 

tions.39 As we have seen, mandatory reporting of such res

recommended by the ACMG; elsewhere (e.g., Germany), su

formation is not routinely reported and may even be discarde

There exists, in fact, a rich literature on the ethics of disclos

not disclosing clinically significant results to participants in m

                                                      

38 See the NCCUSL website, www.nccusl.org, for more information. 

39 See R. Rodney Howell, “We Need Expanded Newborn Screening.” 

and Piero Rinaldo, et al., “Making the Case for Objective Performance M

Newborn Screening by Tandem Mass Spectrometry,” Mental Retardation a

opmental Disabilities Research Reviews 12 (2006): 255-261, p. 255. 

40 R. Rodney Howell, “We Need Expanded Newborn Screening.” p. 18

Rodney J. Pollitt, “International Perspectives on Newborn Screening.” p. 
y jppg

withhold clinical results from research subjects unless there is 

thing that can be done to ameliorate the condition revea

1999, the National Bioethics Advisory Commission (NBAC) 

the following guidance: 

IRBs should develop general guidelines for the disclosu

of the results of research to subjects and require investig

tors to address these issues explicitly in their resear

plans. In general, these guidelines should reflect the pr

sumption that the disclosure of research results to subje

represents an exceptional circumstance. 

Such disclosure should occur only when all of the follow

ing apply: 

a) the findings are scientifically valid and confirmed, 

b) the findings have significant implications for the su

ject’s health concerns, and 

c) a course of action to ameliorate or treat these concerns is read

available.

43

Following this guidance, it would seem appropriate for state 

departments to develop rules governing the disclosure o

disclosure of “incidental” screening results, i.e., positive resu

                                                      

41 See, for example, Barbara P. Fuller, et al., “Privacy in Genetics Resear

ence 285 (1999): 1359-1361; and Daryl Pullman and Kathy Hodgkinson, “

Knowledge and Moral Responsibility: Ambiguity at the Interface of Gen

search and Clinical Practice,” Clinical Genetics 69 (2006): 199-203. 

42 See Ellen W. Clayton, “Incidental Findings in Genetics Research Us

chived DNA,” The Journal of Law, Medicine & Ethics 36 (2008): 286-291. 

43 National Bioethics Advisory Commission, Research Involving Human 

Materials: Ethical Issues and Policy Guidance, vol. 1 (Rockville, MD, 1999); e

added. 
qy 

informed of such incidental findings could be decided by par

connection with the decision about enrolling their children i

screening programs for other poorly understood disorders. A

possible approach would be for the state to inform paren

such incidental findings would be disclosed to them only 

when, as a result of future research, an improved understand

the condition and how it can be effectively treated becomes 

cient to justify adding that condition to the mandatory scr

panel. Obviously, the difficulty and costs of such arrange

would have to be weighed carefully before recommending the

policy for states to follow. In any event, the rules for disclos

non-disclosure of such incidental screening results should b

mulated by each state, and there need be no blanket presum

that the states are ethically obligated to report incidental scr

results to the infant’s physician and parents. 

IV. An Ethical Framework for the Ongoing Expansion o

 Newborn Screening: A Recommendation by the 

 President’s Council on Bioethics 

As we saw in Chapter Two of this white paper, the principl

have governed newborn screening for the past forty years are 

challenged as the states rapidly expand the number of con

for which newborns are routinely screened. It is cause for c

that this progress in the screening and treatment of newbo

serious heritable illnesses has been achieved only at the expe

undermining the prudent principles articulated by Wilson and 

ner. Yet it appears that sensible compromises are possib

would permit uniform, mandatory newborn screening to exp

a reasonable pace in full accordance with classical screening 

ples, side by side with pilot screening programs througho

states, in which disorders that are poorly understood, untre
chusetts approach as a model, an ethically sound approach to 

policy in newborn screening would, in the Council’s opini

clude the following elements. It would: 

1. Reaffirm the essential validity and continuing releva

the classical Wilson-Jungner screening criteria. 

2. Insist that mandatory newborn screening be r

mended to the states only for those disorders that clearly 

the classical criteria. Such a disorder must pose a serious th

the health of the child, its natural history must be well unde

and timely and effective treatment must be available, so th

intervention as a whole is likely to provide a substantial ben

the affected child. 

3. Endorse the view that screening for other condition

fail to meet the classical criteria may be offered by the 

to parents on a voluntary basis under a research para

Such screening programs should be presented forthrightly a

studies, whose benefits and risks to the infant are not certa

for which IRB approval should be obtained in each state. A 

tion included in a pilot screening study should be moved 

mandatory screening panel only if the evidence clearly esta

that it now meets the classical criteria. 

4. Affirm that, when differential diagnosis of some ta

disorders entails detection of other poorly understood 

tions that would not otherwise be suitable candidat

newborn screening, such results need not be transmit

the child’s physician and parents. It should be left to the 

to formulate rules governing whether and when to disclose 

results. 
6. Urge a thorough and continuing re-evaluation of th

orders now recommended for inclusion in the man

screening panel, to ascertain whether they genuinely me

classical criteria that would justify mandatory screening 

newborns, or whether they instead are suitable candida

pilot screening studies. In support of such continui

evaluation, states should be encouraged to collect and share d

the short- and long-term outcomes for children who test p

for a genetic disorder, both those on the mandatory screening 

and those targeted by pilot programs. 

7. Reject any simple application of the “technologic

perative,” i.e., the view that screening for a disorder is ju

by the mere fact that it is detectable via multiplex assay

if the disorder is poorly understood and has no estab

treatment. There should be no presumption that multiplex s

ing platforms are to be used in “full profile mode.” 

\[
107

PERSONAL STATEMENTS 

109

FLOYD E. BLOOM, M.D., AND 

MICHAEL S. GAZZANIGA, PH.D

aving read closely the final draft of the Council’s 

paper on ethical issues in the current expansion o

born screening, we feel obliged to add a statement 

own on the white paper’s tone and scope. 

In our view, while the staff have conducted an admirable and 

prehensive review of the current situation concerning the p

further consequences of continued expansion of mandato

nomic screening capacities, there is also frequent speculation 

those future consequences of screening that goes too far. Wo

about logically possible but low probability outcomes dow

road of the unknown has its limits. Furthermore, we think th

transition into speculating on the adverse consequences for m

practice and the “Doubts About the Power of Genomic Med

(Chapter Three) extends beyond both the needs of this white 

and the implications of the reality of how medicine is practic

day. 

As the white paper notes early on, the expanded uniform scr

panel proposed by the American College of Medical Gene

2005 was “promptly endorsed by the Advisory Committee 

Secretary of Health and Human Services] on Heritable Dis

and Genetic Diseases in Newborns and Children,” and, “b

vember 2008, almost all of the states had adopted the AC

panel of twenty-nine core conditions, and most had initiated s

ing for a majority of the twenty-five secondary conditions.” 

that state of adoption, any practical utility to be gained by 

the Council speak out on the ethical issues that may be 

quences of the transition from a “screen only if you can inte

H
When the white paper states (Chapter Three) that “doubt

been expressed about the potential of genomic studies t

markers for susceptibility to the most common diseases af

mankind, as opposed to the rare metabolic disorders that a

primary target of newborn screening today,” it moves well b

the focus on newborn screening that we took to be the focus 

report. While we acknowledge that it is the potential benefit 

cietal health that drives the quest for identifying the he

factors that can enhance or reduce vulnerabilities to disease 

ways, raising the specter that such genomic information is irr

goes well beyond any existing science and prematurely casts 

on that which will be knowable when more data have been ga

and analyzed. Forestalling knowledge strikes us as a blatantl

intellectual fear of knowledge. The NIH has, after all, already 

pleted the major inventory of the human genome and exten

into inter-individual analysis, established the HapMap conso

and facilitated the early stages of commercialization of co

individual genomes with their unique SNPs and HapMaps

long it may take to convert those efforts into useful treatme

preventions may be unknowable now, but questioning th

seems to us to be well beyond the issues of newborn screenin

The ongoing difficulty of finding genomic markers for co

diseases should not be misinterpreted as an indication tha

markers do not exist. For instance, while some observers m

astounded that the analysis of the human genome to date 

only minor inter-individual bases for identifying the “caus

type 2 Diabetes Mellitus, the heritability of this and other gen

complex medical diseases is scarcely in doubt. 

In addition and with specific regard to the example of Duc

Muscular Dystrophy, it strikes us as illogical to question scr
ggy ppy 

research to reveal better ways to treat earlier to reverse the dis

The white paper poses the question, “Suppose that exp

screening of an infant reveals not a fatal and incurable disea

instead a host of genetic variants, each of which merely confe

vated risk for some condition or other? Who is to say at wha

an uncovered defect becomes serious enough to warrant prev

the birth of other children who might carry it? At what poin

we crossed the line from legitimate family planning to cap

and morally dubious eugenics?” In our view, it may be legitim

pose the question, but it is not appropriate to narrowly foc

consequence of such discoveries to a sinister eugenics de

Knowing the means by which a new discovery confers elevat

may simply be the first step in knowing how to stem that and 

individuals’ journey down an unhealthful pathway to diseas

may eventually lead to new methods of prevention or more 

tive treatments. In raising these questions in this anti-inte

manner, the white paper seems to us to go much further do

road of unknown consequences than the facts offer and 

heuristically constrain the grounds on which to imagine our fu

That overly constrained view of the future potential of genom

sights into disease prevention is further demonstrated in the 

paper’s statement asserting—without any evidence to suppo

the doubtfulness of the scientific perspective: “The presump

modern science, including medical genetics, has always bee

knowledge is fundamentally good for human beings, and th

more we know about ourselves the better we will be able to l

kind of lives we want to live.” 

While we do agree that “there is...the possibility that such 

edge will be misused or misinterpreted,” that has historically 

been the case when new knowledge becomes available, at l
However, when the white paper asserts that “we as a natio

not been in the habit of subjecting individuals to comp

screening merely for research purposes,” we again see anti-sc

thinking at play. The phrase “subjecting individuals to comp

screening” depicts a far more invasive procedure than the sa

of heel stick or cord blood that occurs, while “merely for re

purposes” greatly diminishes the fundamental quest fo

knowledge. To the white paper’s assertion that, “In the wake 

ACMG report and its enthusiastic reception by the states, o

proach to newborn screening seems to be heading into unc

territory,” we ask: should Lewis and Clark have stayed home? 

\[
113

JEAN B. ELSHTAIN, PH.D. 

ongratulations to the staff for this white paper. It is 

clearly written, admiral in its judiciousness, a model o

to lay out complex and controversial issues in a w

opens up rather than shuts down essential debate. 

The basic question is: What ethical principles should guide th

tice of newborn screening in the United States? 

Reading over the paper, I was reminded of the film Gattaca,

great film but an instructive one. Gattaca imagines a future 

dominated by genetic screening. At birth, infants are screen

are either declared “valids” or “invalids.” The “invalids” a

known as “de-gene-erates.” As a result, they do the society’s 

work” and are denied access to what the society values most 

and rewards most generously. The film’s protagonist, by the 

near-sighted—that is his most egregious genetic “sin.” But 

flaw is bound to happen, we learn, because he is a “faith bir

child born the old-fashioned way without the benefit of th

pregnancy rules and regulations of the eugenic society in wh

lives. (Needless to say, these rules and regulations mandate ab

for all “imperfections,” however slight.) 

Let’s turn to our own society at present. We learn that the 

majority of babies born in the United States each year u

screening soon after birth to identify genetic defects that 

cause serious illness if left undetected and untreated.” What 

goal? To detect diseases as early as possible in order that ef

                                                      

1 Columbia Pictures (1997), dir. Andrew Niccol. 

C
orders.” This includes screening for genetic disorders th

extremely rare and for which there is no known treatmen

natural history of such disorders is not well understood. 

In the once prevailing model, the infant’s good was the moral 

screening must be of direct medical benefit to the infant if s

ing itself is to be justified. In the emergent model, newbor

turned into research subjects and the emphasis is no long

well-being of a singular child but the genetic profile of entire 

lations in a situation in which efficacious treatment is not av

for a whole range of potential disorders. To “screen for” is n

same as to “diagnose” a disease. 

With more promiscuous screening, dilemmas involving scr

grow more pronounced and serious—for example, the prob

false positives. As we learn, the large majority of initially p

results for the conditions states now screen for “will turn ou

incorrect.” There are thousands of false positives each yea

extraordinary expense is involved in eliciting such erroneou

leading, and potentially damaging information. Every scr

program is an experiment and, as with any program—whe

the medical, social, or economic realm—there are always 

tended consequences. (So much is this the case that social sc

actually speak of a law of unintended consequences.) 

The white paper takes us through the changing ethical pri

governing newborn screening practices. The consensus tha

pertained—a medical model with the goal of treatment held 

overall raison d'être—has given way, or is giving way, to a re

protocol model. Under the earlier consensus, large-scale pro

were not justified unless resources existed to confirm diagnos

to treat maladies. Screening when no established treatmen

available was considered ethically dubious and rarely justified
language of critics. This is an interesting rhetorical move. Wh

hear “dogma” we think of those who criticize religion as som

uncritically clung to when no “evidence” exists. We are to

dogma involves irrationality and stubborn immovability, esp

from those who stand in the way of “progress.” The rhet

“dogma” is not deployed unthinkingly, one must assume, as 

hoping to break down the earlier ethical and medical con

strive to remove barriers to a vast research protocol involvin

of thousands of human infants. 

Screening within a research paradigm holds forth vague 

prospects of benefits to populations although there is no 

improvement to be realized for any single individual at presen

tifications include a broadened concept of benefit 

rationalizations for allowing technology to dictate the “pa

scope of the expansion of newborn screening.” Benefit remai

hypothetical level. But the claim—held “dogmatically,” one 

suggest—is that broad benefits will be derived at some future 

Critical consideration of knowledge in the absence of treatm

not foregrounded as a major concern. 

My view is that one should not screen in the absence of any 

able treatment or when the benefits of treatment are insign

that families should not be overly burdened with anxiety, 

“vulnerable child syndrome”—a sense that a genetic Sword 

mocles is hanging over their heads. The child’s life m

prematurely medicalized to no good or decent end. To th

must add the extraordinary, runaway costs of such screenin

society in which many are not receiving the immediate, ne

health care they require. 

Babies should not be fodder for biomedical research if ther

available benefit to them as a result of that research. Althou
vor of a radical refashioning that undercuts the historic gravam

infant care? 

Above all, as thoughtful human beings, we cannot and mu

permit what we do in medicine to be driven by the possess

technologies. We must keep technology in its proper place, w

a subordinate one to the overarching goal—if medicine is t

cus—of the well-being of the individual patient. Here, surely

harm remains the surest guide. 

I concur, therefore, with the recommendations proposed 

President’s Council on Bioethics, with this caveat: I would ca

ommendation #3 in somewhat stronger language so that p

understand their baby is being tested as part of a research

medical, protocol. 

\[
117

GILBERT C. MEILAENDER, PH.D

n this white paper examining disputes about the proper 

and scope of newborn screening the Council offers a 

recommendations designed to keep a public health 

(which focuses not on the health of individual patients but 

“health” of society) from swamping and eventually obliter

medical model (which makes an individual patient’s good th

tral concern). The recommendations are judicious, and I am 

to endorse them. Nevertheless, insofar as the key recommen

is more procedural than substantive, I suspect that the recom

dations constitute at best a temporary holding action and ar

to be overcome by a desire for knowledge that has no natural 

We recommend a two-tier approach: mandatory newborn scr

for disorders that constitute a significant danger to health a

which medical treatment is available; voluntary screening o

borns, done under the rubric of research and done only with informed co

their parents, for other disorders about which relatively little is 

or for which no medical treatment is currently available. 

Advocates of research might raise an obvious worry about t

proach: What if few parents consent to have their new

screened for disorders that cannot currently be treated? Wou

not slow the progress of knowledge and limit the treatments 

able to future sufferers? 

But, the white paper assures us, there is little need to fear 

result. In most states parents are currently permitted to opt 

otherwise mandatory newborn screening, but few do so. The 

ber of parents who opt out is comparable to the number of p

who refuse to consent in those few states where newborn scr

I
requiring informed parental consent will adequately protec

born children without hindering at all the progress of resear

shall we wonder whether the procedural requirement of inf

consent, relatively inconsequential as it seems to be here, e

ages us not to think about some of the deeper issues burie

discussion of mandatory newborn screening? 

Inclining as I do to the latter possibility, I offer here a ver

discussion aimed at calling such issues to mind. In some of 

lier work, especially in Beyond Therapy, the Council has already 

attention to the way in which our desires for better (healthi

happier) children and longer life, having few limits, may und

essential aspects of our humanity. Those concerns remain r

here. We should not ignore the way in which an expanded pr

of newborn screening touches and transforms the relation b

parents and children, nor should we overlook the questions i

about the use of infants in the cause of medical research. 

Expanded newborn screening is essentially research carried o

the public good, not the good of the infants being screened. 

be desirable to gain such knowledge, but it is not imperat

“Philosophical Reflections on Experimenting With Human 

jects,” a classic essay in bioethics first published in 1969

Jonas noted the difference. Sometimes it is imperative that a 

avoid disaster; hence, for example, we conscript soldiers to 

But we do not ordinarily conscript experimental subjects, b

however much we value the knowledge gained through resear

do not think ourselves obligated to acquire it. We seek volu

not conscripts, in the cause of medical progress. 

For that reason, Jonas argued, rather than using those who m

most readily available as handy research subjects, we should 

pecially reluctant to use them—governing ourselves in accor
p

Also at stake, though, is something deeper than a question 

search ethics alone. The white paper notes that man

screening of disorders for which no treatment currently exis

foster a kind of parental overprotectiveness, distorting the r

between the generations. We might go farther and ask: How 

it not foster such an attitude? To seek to protect one’s c

from harm is part of what it means to be a good father or m

yet, what will teach us or who will help us know when to sto

always possible to suppose that knowledge which cannot 

moment benefit one’s child may be useful in the future—an

therefore be sought. Hence, we press to know more and mo

we do so with a good conscience, secure in the knowledge th

concern is for our children. Indeed, rather than taking com

the fact that ninety-seven percent of parents are likely to con

the use of their newborn children in research of no thera

value for those children, we might wonder whether in our 

they really feel free to refuse when the lure of increased kno

is held before them. 

Giving parents more choices does not necessarily give them 

freedom to carry out their parental duties. Sometimes, par

cally, it constrains them in new ways. How many parents ar

prepared to say no to an offer of knowledge about their 

health, even if that knowledge can have no impact at all 

medical care of the child? How many want to shoulder the b

of responsibility involved in declining to know whatever 

known about the health of their child? A request for informe

sent suggests that we are free; the cultural force of our comm

to increased scientific knowledge belies that seeming freedom

Ours is a culture that—having largely forgotten the stories 

Garden of Eden and Prometheus—has little appreciation f
knowledge and constrained in unexpected ways by the very c

set before us, we may not be as free as we suppose to give gen

parental care to our children—and the line between screenin

is mandatory and screening that is voluntary may be more b

than we are eager to acknowledge. 

It is a sign of ill health—in a society, as in an individual—to 

too single-mindedly to health. I doubt that a requirement of c

is by itself sufficient to save us from the tyranny of our de

know more, to be healthy and happy—indeed, to save ou

and our children from the evils we fear. Therefore, this Co

recommendations—judicious and cautious as they are—wi

considerable cultural support if they are actually to achiev

aims. 

\[
121

CARL E. SCHNEIDER, J.D. 

he Council’s white paper perceptively surveys and 

describes a complex problem. The white paper sk

analyzes the problem by recruiting the approaches tha

become standard in bioethical thought. Those approaches inc

tight focus on the rights of the patient or research subject and 

tent preference for using informed consent and the IRB sys

protect those rights. These standard approaches provide o

nificant way to think about bioethics generally and ne

screening particularly. Standard approaches have dominate

ethics, not least because it is a movement more than a discip

regulatory regime more than a field of inquiry, and even a 

more than a question. But might a less conventional approa

only offer insights into newborn screening but also deepen a

fresh a discourse in which dogmatism has always been a dang

us try the experiment. 

Screening calls on scarce social and scarce personal resourc

what if we ask how good stewards of such resources should 

about such calls? The white paper impressively canvasses th

and benefits of newborn screening and rightly says that scree

wrong if its costs (economic, social, and personal) exceed its 

fits. But even if its benefits exceed its costs, screening would 

a poor investment if other investments are more rewardin

example, HHS reports that the United States “ranks 27th 

industrialized countries” in infant mortality and that “disp

remain among racial and ethnic groups in many measures of 

nal and child health.” Dollars spent changing these figures 

T
mands informed consent to screening, but to learn enough to 

wise choices parents must devote resources—attention, energ

medical-consultation opportunities—to that education. If ne

screening were all new parents had to think about, imposin

education on them could make sense. But of course new p

have more on their minds. And they should. When I asked a 

practice physician where newborn screening fell in his list of 

tional priorities for new parents, he tried to be tactful. He st

to teach parents to bring babies in for attention when they 

fever, not to give babies water, to put babies to sleep on thei

and much else that is not obvious but saves lives.2

 

 

Telling parents to spend resources learning about newborn s

ing looks even less prudent given the sobering but ever-mo

evidence that informed consent cannot achieve the goal set f

equipping people to reason their way to well-founded and 

considered medical decisions. Legions of able and earnest res

ers have for decades labored nobly to make informed consent 

but even after the most arduous education patients regularly 

only a fraction of what they need to make a sound decision

should not be surprising. Teaching is hard. Learning is hard. 

So once again we are brought back to stewardship: People ca

learn so much; governments can only teach so much. Both n

allocate their educational efforts wisely. (As Alfred North 

head put it, “Operations of thought are like cavalry charge

                                                      

1 For helpful reflections on this likelihood, see Mary Ann Baily and Tho

Murray, “Ethics, Evidence, and Cost in Newborn Screening,” Hastings C

port 38 (2008): 23-31. 

2 See Robert C. Langan, “Discharge Procedures for Healthy Newborns,” A

Family Physician 73 (2006): 849-852. 

3 Carl E. Schneider, “After Autonomy,” Wake Forest Law Review 41 (200

444. 
p 

ture of bioethical wisdom—IRB review. The IRB system 

experiment in censorship on a remarkable scale, but is the 

justifiable? While the system’s proponents recite scandals, 

attempts to show systematically that the IRB system does 

good than harm are hard to find. Yet a distressingly strong ca

be made that the IRB system is an improvident steward of 

sources it commands—that it is structured to make capricio

unwise decisions; that it delays, damages, and stops researc

could save lives and relieve suffering; that it institutionalizes 

poverished ethics; that it imposes orthodoxy where there sho

freedom; that it corrodes the values the First Amendment pr

that it flouts the most essential principles of due process; tha

lawless enterprise that evades democratic accountability. Thes

sibilities may seem startling, but more startling is that so pot

institution has never been held to the standards of justificat

expect of any exercise of the state’s coercive power. 

The stewardship approach leads us to one more question: I

born screening is needed, how should it be instituted? The i

not whether parents may exempt children from screening

whether the rule should be that children are screened unles

parents opt out or that children are not screened unless the

ents opt in. This is a critical question because a large literatu

us that even when people care about a decision (like contribu

retirement accounts), they frequently leave themselves wh

default rules put them. 

So which default rule should govern newborn screening? Th

pends on two things. First, which rule would best reflect p

preferences? That is, which rule is likeliest to leave parents 

they want to be? The Council’s white paper persuasively a

that question. Given a choice in surveys and in real life, pare

most all choose screening. So if conserving scarce soci
it protects newborns and their families and that it promote

able research. Assuming that these arguments are reasonab

opt-out rule again is preferable. One more social interest po

that direction: an opt-out rule attributes to parents a willingn

assist in medical research when they can do so at vanishingly 

risk. An opt-out rule assumes that parents recognize that th

their children benefit from generations of participation in re

and can repay their debt by participating in research that w

families yet to come. An opt-out rule thus stands in the long A

can tradition Tocqueville described: “The free institutions wh

inhabitants of the United States possess, and the political rig

which they make so much use, remind every citizen, and in a 

sand ways, that he lives in society. They every instant impres

his mind the notion that it is the duty as well as the interest o

to make themselves useful to their fellow creatures; and as h

no particular ground of animosity to them, since he is never 

their master or their slave, his heart readily leans to the s

kindness.” 

The Council’s mandate is to explore fundamental issues i

ethics. The Council’s white paper does so by carefull

insightfully applying the principles of bioethics that have b

canonical. This brief statement is a case study intended to a

the most allusive and possibly elusive way—whether the tim

come to re-evaluate those principles, to identify their limits, 

supplement them with a richer range of ethical wisdom. 

\[
125 

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