PKU and Beyond: When Do Costs Exceed Benefits?

(1)

TABLE II

THE EFFECT OF DISEASE PREVALENCE ON NUMBER OF OVER

REFERRALS AND UNDER-REFERRALS ASSUMING A TEST

WITH 90% SENSITIVITY AND 90% SPECIFICITY

Diseased Nondisensed Total

20% Prevalence

Test Positive 180 80 260

Test Negative 20 720 740

Total 200 800 1,000

1% Prevalence

Test Positive 9 99 108

Test Negative 1 891 892

Total 10 990 1,000

calibration of instruments or better training of personnel will improve both sensitivity and speci-ficity.

3. Choosing a different test with greater sensi-tivity or specificity.

4. Screening simultaneously with two separate tests and accepting as positive those with either test positive will increase the sensitivity but may decrease the specificity.

5. Screening simultaneously with two separate tests and accepting as positive only those with both tests positive will increase the specificity but may reduce the sensitivity.

6. If unreliability of the test contributes to

lower validity, rescreening with the same test and accepting as positive only those with two positive tests will increase the specificity of the test and decrease the number of over referrals.

CONCLUSION

The availability of a suitable screening test does not justify screening for a disease unless the dis-ease is important, relatively prevalent, and ame-nable to early treatment. Screening for a disease which has the necessary characteristics cannot be justified unless there is an acceptable, reliable and valid test which can be carried out at reasonable cost.

Screening which is carried out without knowl-edge and consideration of these criteria is likely to be wasteful of scarce medical resources and may actually do more harm than good.

REFERENCES

1. Wilson, J. M. C., and Jugner, C.: Principles and Practice of Screening for Disease. Public Health Papers

*34. Geneva: World Health Organization, 1968.

2. Frankenburg, W. K., and Camp, B. W.: Pediatric Screen-ing Tests. Springfield, Ill.: Charles C Thomas, Publisher, in press.

3. Thorner, R. M., and Remein, Q. R.: Principles and Proce-dures in the Evaluation of Screening for Disease,

Public Health Monograph No. 67. U.S. Public

Health Service Publication No.846, Washington,

D.C.

PKU and Beyond:

When

Do Costs

Exceed

Benefits?

Charles R. Scriver, M.D.

The “first law of screening” stresses that effec-tive measures must reduce “costs.” As in all

yen-tures, those who pay the piper can expect to call

the tune. Whether the concept of cost effective-ness should dominate all decisions about screening for hereditary metabolic disease has been chal-lenged both by the pipers and by those who pay; but to ignore all together this position would be to live again in Hamelin town. Therefore, I will try to clarify several views of cost which are of

inter-est to those who plan or engage in screening for genetic disease.25

THE ECONOMIC VIEW OF COSTS

Cost avoidance receives the principal emphasis because the benefits of screening are hard to

ADDRESS FOR REPRINTS: The McGill

University-Mon-treal Children’s Hospital Research Institute, 2300 Tupper

(2)

PEDIATRICS FOR THE CLINICIAN 617 price. The monetary costs resulting from

screen-ing and treatment are to be weighed against those incurred when such preventive practices do not take place. We could, indeed, avert the monetary cost to society of phenylketonuria (PKU) by elimi-nating chronic care institutions for the mentally retarded; at one time PKU patients comprised 1% of their residents. Thankfully, no one has consid-ered this to be an acceptable option. Instead we are pleased to find that one dollar spent for the screening and treatment of PKU is more than bal-anced by a saving of $4 in institutional and other care which would otherwise be given to non-screened, untreated, retarded PKU patients.6

In the economic view, only real costs are con-sidered. These include the specific cost of screen-ing and treatment which prevents the full expres-sion of the disease; this cost should be weighed against the specific life cost of traditional or new

methods of dealing with the disease without

screening.

In the economic model, benefits and costs to which dollar values cannot easily be attributed are

ignored. But decisions about screening are

fre-quently adumbrated by such considerations. For example: benefits such as the ultimate social worth of the individual protected from disease; his earning power as an adult; the reduction of ad-verse psychologic and social effects on his family; the psychological rewards to health workers who help ensure a normal life rather than give custo-dial care for a hopeless life, all weigh in the proc-ess of decision. Against these assets, there are non-dollar debits, for example, the worry and in-convenience to parents whose normal children require further testing because of false-positive screening tests; the cost, inconvenience and actual danger of treatment when screening test results are misinterpreted and children mismanaged; the diversion of professional time and interest from other health activities which might have much higher returns in social benefit for the time and

skill invested.

THE CONCEPT OF MARGINAL COST

Once a screening system has been established, its basic operating cost for equipment, materials and personnel is predictable from year to year, whatever the volume of work. In fact the operat-ing cost per test decreases as the number of tests increases. It is also evident that the cost for any ad-ditional test procedure in the same program will incur a marginal operating cost since the same sys-tem of collecting specimens, recording necessary demographic data, transporting specimens, and recording and reporting results can be used. The

marginal cost comprises only the new materials and equipment required for the new test. As a

re-sult, screening tests with relatively low yield can

be included economically in such programs. For example, the screening program in the Province of Quebec includes blood tests for PKU, tyrosine-mia and galactosemia and additional urine tests which will identify up to 30 of the rarer abnor-malities of intermediary metabolism. The cost per “test” or per disease screened is consequently much less than if we were to screen for PKU alone and the cost of finding children with one of several significant abnormalities is only slightly more than in the screening program restricted to PKU.

CHANGING THE COST BALANCE BY

SELECTION OF SPECIAL “AT RISK”

POPULATIONS

Costs calculated from “average” populations may not be relevant for a particular geographic region or ethnic group. For example, screening for the Tay-Sachs heterozygote among the

Ashkena-zim will yield

a carrier

frequency

of one in 30

per-sons, and identify one in 900 couples to whom an affected child might be born. Outside this com-munity the carrier frequency is one in 300, and

proportion

of couples

capable

of producing

an

affected child is one in 90,000. The cost of

identi-fying an “at risk” couple is thus 100 times greater

in the general population than in the Ashkenazim; screening can reasonably be encouraged for the latter community but not for the general popula-tion.

A similar perspective applies to other groups which have been genetically “isolated” by culture or geography. In one such population in Northeast

Quebec,7

about

one

live birth

per 650 has hered-itary tyrosinemia, a trait which is extremely rare elsewhere in North America.

SENSITIVITY AND SPECIFICITY OF THE

TEST AFFECT ITS COST

Specificity of the screening test is defined as the

percent

of healthy

individuals

excluded

from

de-tection. Low specificity leads to high screening costs, consumed in tracing healthy subjects for

fol-low-up

tests.

Sensitivity is defined as the percent of diseased patients discovered by the test. At the end of the first decade of PKU screening, we learn that some of the PKU screening tests have lower sensitivity for the female neonate with PKU than for the males.8 “Costs” in this

example

has

a sex

ratio!

Careful selection and application of the screening

test is essential to reduce its technical costs, and to maintain high specificity and sensitivity.

at Viet Nam:AAP Sponsored on September 8, 2020

www.aappublications.org/news

(3)

1000

/

“o-c 0 a, a, C., One harmful

gene every: 100 10

4

Sickle cell Recessive anaemia,

inborn errors thalassaeinia

lO#{149} lO- 10.2 10.’

Frequency of the gene at the initial generation

10000 1000

I

Very rare

Rare dominant recessive disorders disorders

Fic. 1. Time in generations (ordinate) required for doubling of the frequency of different types of lethal or very low fit-ness genes (abscissal) when reproduction of affected patients becomes possible through the application of screening and treatment (mutation rates of about 10 are assumed). Pub-lished with permission from WHO Technical Report *497,

Geneva, 1973.

THE “COUNSELLING COST” OR THE

“COST OF CLASSIFICATION ERRORS”

In as much as most screening tests have imper-fect sensitivity and specificity, some “normal” people will be classified wrongly as “abnormal” and some “abnorrnals” will escape detection. Mis-classification has undesirable consequences which must be counted as costs: for the normal subject classified wrongly as “abnormal” there will be in-convenience, worry and personal suffering, the potential social stigma from being “labelled,” as well as financial costs to the family, the individual and society resulting from mislabeling. Similarly, misclassification of abnormals as “normal” has costs, including loss of public confidence in the program, the cost of finding and managing abnor-mals not detected by screening and the burden of untreated disease. Decisions about what tests to use and how to apply them must be based on as-sumptions about which classification error is more serious or costly.9

This issue becomes especially relevant when we attempt, for purposes of genetic counselling, to discriminate heterozygous carriers from persons

who do not carry the gene in question. In such in-stances the salient test results are quantitative, and statistical methods must be used to recognize the abnormal test. Our studies of carrier detection in PKU and Tay-Sachs disease indicate that the cost of not detecting and not counselling (abdi-cating responsibility for classification) always ex-ceeds the cost of testing and counselling.9 Better statistical methods for discriminant analysis, the use of multiple tests rather than a single test, and meticulous attention to test methodology all serve to reduce the counselling error and its costs.

GENETIC COSTS TO THE SPECIES

As prevention, treatment and rehabilitation of persons with deleterious genetic traits increasing-ly allows such persons to survive and to reproduce, the frequency of such genes in the population will increase. The time in generations necessary to double the frequency of a mutant gene after screening and treatment permit reproduction of affected persons is shown in Figure 1. But is this a real threat? Screening and treatment have made it possible for affected persons, who once rocked aimlessly in forlorn wards outside Hamelin’s walls to ply their trades usefully on its streets.

REFERENCES

1. Wilson, J.M. C., and Jungner, G.: Principles and Practice of Screening for Disease. Public Health Papers

*34. Geneva: World Health Organization, 1968.

2. Screening for Inborn Errors of Metabolism. Geneva:

World Health Organization Technical Report

Se-ries *401, 1968.

3. Harris, M. (ed.): Early Diagnosis of Human Genetic De-fects: Scientific and Ethical Considerations.

Fog-arty Intemat. Centre Proc. No. 6 HEW. Pub.

72-75, Washington, D.C., 1971.

4.

Clow, C. L., Fraser, F. C., Laberge, C., and Scriver, C. R.: On the application of knowledge to the patient with genetic disease. Progr. Med. Genet., 9:159,

1973.

5. Genetic Disorders: Prevention, Treatment and Rehabili-tation. Geneva: World Health Organization Tech-nical Report Series *497, 1972.

6. Webb, J.F.: Advisory Committee on Inborn Errors of Me-tabolism to the Ministry of Health: PKU screening -Is it worth it? CMA Journal, 108:328, 1973. 7. Laberge, C.: Hereditary tyrosinemia in a French

Canadi-an isolate. Amer. J. Hum. Genet., 21:36, 1969.

8. Hsia, D. Y. Y.: Phenylketonuria: Clinical, genetic and biochemical aspects. In Primrose, D. A. A. (ed): Proceedings of the 2nd Congress of the Interna-tional Association for the Scientific Study of

Men-tal Deficiency, Warsaw, 1970. Warsaw: Polish

Med. Pub., pp. 105-113, 1971.

9. Gold, R. J.M., Maag, U. R., Neal, J.L., and Scnver, C. L.: The use of biochemical data in screening for

(4)

PEDIATRICS FOR THE CLINICIAN 619 ACKNOWLEDGMENTS

I am grateful, in particular, to Mrs. Carol Clow and Dr. Reynold Gold whose perspectives on screening are

invalu-able to me; also to my many colleagues in the Quebec Net-work of Genetic Medicine with whom screening for genetic disease has been made into something immensely practical.

Current

Status

of Screening

Children

for Urinary

Tract

Infections

Calvin M. Kunin, M.D.

There is ample evidence that significant

bacte-riuria is frequent enough and procedures for mass

screening are sufficiently developed to enable this

country to mount a large scale program directed

to the early detection of urinary tract infections. Information is now available on the epidemiology of bacteriuria, the frequency of associated structu-ral abnormalities and methods to provide effec-tive management. It is also clear that most female children with urinary tract infection generally will have a good prognosis. Few will develop end-stage renal failure, but symptomatic infection is commonly associated with considerable morbidi-ty. Unfortunately, it is not as yet possible to pre-dict which child is at high risk of developing seri-ous complications without searching for structural or neurologic abnormalities or by following mdi-vidual patterns of recurrence. The ultimate im-pact on health and longevity is unknown even using data from the most structured programs. There is also the danger that mass programs may lead to false hope and eventual disillusionment if they are limited to detect infection and do not provide for further diagnostic, therapeutic and long-term follow-up of patients.

For these reasons, urinary tract infection detec-tion programs must be designed in relation to the realities of the current medical care system, the goals should be clearly defined and the expected result be stated honestly.

fection and its complications so common in fe-males throughout life. The other is to detect the population (often with anatomical abnormalities) at risk of developing pyelonephritis and

subse-quent

renal

damage.

These

goals

can

readily

be

paired

since

even

though

the

risk may

be low

of

developing

important

renal

functional

damage

from

infection,

prevention

of morbidity

is

suffi-ciently important to warrant preventive mea-sures.

One

should

never

try

to justify

screening

pro-grams on the sole grounds that they satisfy a public

desire

for a community

health

project

or to

“edu-cate”

the public

in order

to raise

funds

for a cause,

no matter

how

worthwhile.

ORDER OF PRIORITIES

There

is no point

in developing

mass

screening

programs to detect asymptomatic bacteriuria if

the bulk

of physicians

in a community

who

would

care

for the patients

are not interested

or trained

to manage

them

well.

Furthermore,

there

may

al-ready

be large

numbers

of patients

with

sympto-matic

infection

who

are

not

being

adequately

evaluated, are not receiving proper therapy or are

not followed

systematically.

The

first priority,

in

any national program must, therefore, be to en-sure sufficient physician education

to

provide

proper

care

for the symptomatic

patient.

The

sec-AIMS OF THE PROGRAM

There are two major reasons for screening

chil-dren

for urinary

tract

infection.

One is to prevent the considerable morbidity from symptomatic

in-ADDRESS FOR REPRINTS: Veterans Administration

Hos-pital, 2500 Overlook Terrace, Madison, Wisconsin 53705.

(5)

1974;54;616

Pediatrics

Charles R. Scriver

PKU and Beyond: When Do Costs Exceed Benefits?

Services

Updated Information &

http://pediatrics.aappublications.org/content/54/5/616

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or in its

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

(6)