Where might the blood bank director and the head of drug treatment want the cutoff point to be for each program?

In December 1982, a report in the MMWR
described three persons who had developed
acquired immunodeficiency syndrome (AIDS) but
who had neither of the previously known risk
factors for the disease: homosexual/bisexual
activity with numerous partners and intravenous
drug use. These three persons had previously
received whole-blood transfusions. By 1983,
widespread recognition of the problem of
transfusion-related AIDS led to controversial
recommendations that persons in known
high-risk groups voluntarily defer from donating
blood. In June 1984, after the discovery of the
human immunodeficiency virus (HIV), five
companies were licensed to produce
enzyme-linked immunosorbent assay (EIA, then
called ELISA) test kits for detecting HIV
antibody. A Food and Drug Administration
(FDA) spokesman stated that, “…getting this test
out to the blood banks is our No. 1 priority….”
Blood bank directors were anxiously waiting to
start screening blood with the new test until
March 2, 1985, the date the first test kit was
approved by the FDA.
In the pre-licensure evaluation, sensitivity and
specificity of the test kits were estimated using
blood samples from four groups: those with
AIDS by CDC criteria, those with other
symptoms and signs of HIV infection, those with
various autoimmune disorders and neoplastic
diseases that could give a false-positive test
result, and presumably healthy blood and
plasma donors.
Numerous complex issues were discussed even
before licensure. Among them were
understanding the magnitude of the problem of
false-positive test results, and determining
whether test-positive blood donors should be
notified.
It is now March 2, 1985. The first HIV antibody
test kits will arrive in blood banks in the state in a
few hours. Meeting with State Epidemiologist to
discuss the appropriate use of this test are the
Commissioner of Health, the medical director of
the regional blood bank, and the chief of the
State Drug Abuse Commission.
To help in the discussions, the State
Epidemiologist turns to pre-licensure information
regarding the sensitivity and specificity of test
kit A. The information indicates that the
sensitivity of test kit A is 95.0% (0.95) and the
specificity is 98.0% (0.98). These and related
measures are reviewed below.
NOTES ON SENSITIVITY AND SPECIFICITY
Actual antibody status
Test result Present Absent Total
Positive True positive (A) False positive (B) All positive tests (A+B)
Negative False negative (C) True negative (D) All negative tests (C+D)
Total All with antibody
(A+C)
All without antibody
(B+D)
Total (A+B+C+D)
Sensitivity – the probability that the test result will
be positive when administered to persons who
actually have the antibody.
= true positives / all with antibody
Algebraically, sensitivity = A / (A+C)
Specificity – the probability that the test result will
be negative when administered to persons who
are actually without the antibody.
= true negatives / all without antibody
Algebraically, specificity = D / (B+D).
Predictive-value positive (PVP) – the probability
that a person with a positive screening test result
actually has the antibody.
= true positives / all with positive test
Algebraically, PVP = A / (A+B).
Predictive-value negative (PVN) – the probability
that a person with a negative screening test
result actually does not have the antibody.
= true negatives / all with negative test
Algebraically, PVN = D / (C+D).
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 3
Question 1: With this information, by constructing a 2-by-2 table, calculate the predictive-value
positive and predictive-value negative of the EIA in a hypothetical population of
1,000,000 blood donors. Using a separate 2-by-2 table, calculate PVP and PVN for a
population of 1,000 drug users. Assume that the actual prevalence of HIV antibody
among blood donors is 0.04% (0.0004) and that of intravenous drug users is 10.0%
(0.10).
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 4
The blood bank director wants assistance in
evaluating the EIA as a test for screening donor
blood in the state. In particular, she is
concerned about the possibility that some
antibody-positive units will be missed by the test,
and she wonders about false-positive test results
since she is under pressure to develop a
notification procedure for EIA-positive donors.
Question 2: Do you think that the EIA is a good screening test for the blood bank? What would you
recommend to the blood bank director about notification of EIA-positive blood donors?
The chief of the State Drug Abuse Commission
has noticed a dramatic increase in AIDS among
clients in his intravenous-drug-abuse treatment
programs. For planning purposes, he wants to
do a voluntary HIV antibody seroprevalence
survey of intravenous-drug-abuse clients and
would like to assess the feasibility of using the
test results as part of behavior-modification
counseling.
Question 3: Do you think that the EIA performs well enough to justify informing test-positive clients in
the drug abuse clinics that they are positive for HIV?
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 5
Question 4: If sensitivity and specificity remain constant, what is the relationship of prevalence to
predictive-value positive and predictive-value negative?
EIA results are recorded as optical-density (OD)
ratios. The OD ratio is the ratio of absorbance of
the tested sample to the absorbance of a control
sample. The greater the OD ratio, the more
“positive” is the test result. The EIA, as
with most other screening tests, is not perfect;
there is some overlap of optical-density ratios of
samples that are actually antibody positive and
those that are actually antibody negative. This is
illustrated in the following figure.
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 6
Hypothetical distribution of results on an EIA for HIV,
by actual antibody status
Number of persons
OD Ratio
C A B
Actually
without
antibody
Actually
have
antibody
Establishing the cutoff value to define a positive
test result from a negative one is somewhat
arbitrary. Suppose that the test manufacturer
intiially considered that optical density ratios
greater than “A” on the above figure would be
called positive.
Question 5: In terms of sensitivity and specificity, what happens if you raise the cutoff from “A” to “B”?
Question 6: In terms of sensitivity and specificity, what happens if you lower the cutoff from “A” to
“C”?
Question 7: From what you know now, what is the relationship between sensitivity and specificity of a
screening test.
Question 8: Where might the blood bank director and the head of drug treatment want the cutoff point
to be for each program? Who would probably want a lower cutoff value?
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 7
PART II
The blood bank director is concerned that,
because of the low predictive-value positive of
the EIA in the blood donor population, the blood
bank personnel cannot properly inform those
who are EIA positive of their actual antibody
status. For this reason, he wishes to evaluate
the Western blot test as a confirmatory test for
HIV antibody.
The Western blot test identifies antibodies to
specific proteins associated with the human
immunodeficiency virus. The Western blot is the
most widely used secondary test to detect HIV
antibody because its specificity exceeds 99.99%;
however, it is not used as a primary screening
test because it is expensive and technically
difficult to perform. Its sensitivity is
thought to be lower than that of the EIA.
Because the Western blot test is not yet
generally available, the blood bank director is
wondering whether the initial EIA-positive results
can be confirmed by repeating the EIA and by
considering persons to have the antibody only if
results of both tests are positive.
The State Epidemiologist suggests that they
compare the performance of the repeat EIA and
the Western blot as confirmatory tests. To do
this, they will use the earlier hypothetical sample
of 1,000,000 blood donors. They assume that
serum specimens that are initially positive by EIA
are then split into two portions; a repeat EIA is
performed on one portion and a Western blot on
the other portion.
Question 9: What is the actual antibody prevalence in the population of persons whose blood samples
will undergo a second test?
Question 10: Calculate the predictive-value positive of the two sequences of tests: EIA-EIA and
EIA-Western blot. Assume that the sensitivity and specificity of the EIA are 95.0% and
98.0%, respectively. Assume that the sensitivity and specificity of the Western blot are
80.0% and 99.99%, respectively. Also assume that the tests are independent, even
though they may not be (e.g., those with cross-reactive proteins are likely to cross-react
each time).
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 8
Question 11: Why does the predictive-value positive increase so dramatically with the addition of a
second test? Why is the predictive value positive higher for the EIA-WB sequence than
for the EIA-EIA sequence?
It is now July 1987 and the Governor has asked
the State Epidemiologist to evaluate a proposed
premarital HIV-antibody-screening program. A
bill to establish the program is to be presented to
the state legislature tomorrow. An estimated
60,000 people will get married in the state in the
next year. The proposed legislation requires that
each prospective bride and groom submit a
blood sample for EIA testing. Samples that test
positive by EIA will undergo confirmatory
Western blot testing.
The legislation describes the goal of the
screening program to be to decrease inadvertent
perinatal or sexual HIV transmission by
determining who among those to be married are
probably infected with the virus.
Question 12: What criteria would you consider in evaluating this proposed screening program?
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 9
The following two tables show the results of the
testing, assuming that persons getting married
have the same actual HIV antibody prevalence
as blood donors (0.04%). In 1987, the sensitivity
and specificity of the improved EIA
Test Kit A available at the time were 97.0% and
99.8%, respectively. The Western blot sensitivity
and specificity were 95.0% and 99.99%,
respectively.
Actual antibody status
Initial EIA Present Absent Total
Positive 23 120 143 (These 143 will undergo
Western blot testing)
Negative 1 59,856 59,857
Total 24 59,976 60,000
Follow-up Western blot Present Absent Total
Positive 22 0 22
Negative 1 120 121
Total 23 120 143
With sequential tests: Sensitivity of 92%
Specificity of 100%
Predictive-value positive of 100%
Question 13: Compute the cost of the screening program. Assume a cost of $50.00 for every initial
EIA test ($10.00 lab fee and $40.00 health-care-provider visit) and an additional
$100.00 for EIA-positive persons who will need additional testing. What is the cost of
the screening program in the next year? What is the cost per identified
antibody-positive person?
Question 14: What is your final recommendation to the Governor?
CDC EIS Summer Course, 2002: Screening for HIV – Student’s Guide Page 10
THE NEW YORK TIMES NATIONAL SUNDAY, JUNE 25, 1989
Illinois Legislature Repeals Requirement for Prenuptial AIDS Tests
By ISABEL WILKERSON
Special to The New York Times
SPRINGFIELD, ILL., June 23 – At the
urging of health officials and AIDS
specialists, the Illinois Legislature
repealed Friday night the only law in the
country requiring prenuptial testing for
the AIDS virus.
The measure now goes to Gov. James
R. Thompson. He has consistently
declined comment on whether he will
sign it, although pressure on him to do so
is intense, including that of his State
Health Director, Dr. Bernard Turnock.
A similar testing law in Louisiana was
repealed last year, six months after it
took effect.
“We made a mistake and we ought to
admit it,”said Bill Marovitz, a State
Senator from Chicago, urging his
colleagues to overturn the testing law.
Prenuptial testing began in Illinois in
January 1988 over the strong objection
of both the Illinois Department of Public
Health and AIDS policy experts.
They said it was an inefficient and
expensive way to identify carriers of the
virus and diverted already scarce
resources from those most at risk.
44 Positive Out of 221,000
Since then, the tests, which detect the
antibodies that indicate infection with the
human immunodeficiency virus which
cases AIDS, have turned up few cases of
the disease. Of the 221,000 people who
took marriage vows in Illinois since the
law took effect, 44 were infected with
the HIV virus, tests indicated, and health
officials suspect that nearly a dozen of
those results may be false. Since the
testing was confidential, health officials
do not know the outcome of these cases.
The tests have also led thousands of
people to leave the state to get married
and undetermined numbers of others to
put off marriage altogether, health
officials said.
Marriages in Illinois fell by nearly a
quarter from 99,212 in 1987 to 77,729
in 1988, although the numbers are up
slightly so far this year over 1988.
AIDS specialists hailed the repel
legislation as long overdue. “It’s a ‘wetold-
you-so’ situation,” said Andrew
Deppe, a spokesman for the AIDS
Foundation of Chicago. “Illinois has
become a national laughingstock. We’ve
had to spend our energy putting out
brush fires instead of working on
prevention.”
But Penny Pullen, a Republican State
Representative from suburban Cook
County, who sponsored the prenuptial
AIDS testing bill, said repeal of the law
would hurt the state’s efforts to curb the
spread of the virus, “This is a major
mistake,” Ms.Pullen said. “This will send
an unfortunate message to the people of
Illinois and the rest of the nation that
AIDS is not as serious an epidemic as it
was two years ago. And that message is a
lie.”
Fewer Than Predicted
She pointed to an increase in the
number of positive test results in the first
half of this year as evidence that the law
was working. So far this year, the tests
have indicated 18 cases of the AIDS
virus among 66,500 newly betrothed
people, as against 8 cases among 59,000
people in the same period last year, the
Illinois Department of Public Health
said.
But officials of the health department
said that even with that increase, the
agency had found far fewer case in the
18 months of mandatory testing than the
120 cases it originally predicted would
be found each year.
The agency also found that the rate of
infection among engaged couple’s was
comparable to those of other low-risks
groups. Engaged couples in Illinois and
blood donors, both groups considered at
very low risk, have rates of infection of
about 2 per 10,000.
“The overall rate among these couples
is close to the lowest rate ever recorded in
this country.” said Tom Schafer, a
spokesman for the Illinois Department of
Public Health.
While even critics say the law has
been useful in raising awareness of the
AIDS epidemic, state health officials said
it was an expensive way to detect carriers
of the virus . The test costs each person
from $30 to $125, depending on whether
testing is done in clinics or in a doctor’s
office and whether follow-up testing is
required. The total cost for Illinois couples
last year was $5.4 million, or about
$209,00 for each case of HIV infection
detected.
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 11
Appendix 1
The following 10 principles of successful mass screening programs were proposed by Wilson and Jungner
of the World Health Organization in 1968:
1. The condition being sought is an important health problem for the individual and the community.
2. There is an acceptable form of treatment for patients with recognizable disease.
3. The natural history of the condition, including its development from latent to declared disease, is
adequately understood;
4. There is a recognizable latent or early symptomatic stage.
5. There is a suitable screening test or examination for detecting the disease at the latent or early
symptomatic stage, and this test is acceptable to the population.
6. The facilities required for diagnosis and treatment of patients revealed by the screening program are
available.
7. There is an agreed policy on whom to treat as patients.
8. Treatment at the pre-symptomatic, borderline stage of a disease favorably influences its course and
prognosis.
9. The cost of the screening program (which would include the cost of diagnosis and treatment) is
economically balanced in relation to possible expenditure on medical care as a whole.
10. Case-finding is a continuing process, not a “once and for all” project.
References – Screening for HIV
1. Check WA. Preventing AIDS transmission: should blood donors be screened? JAMA 1983;
249:567-70.
2. Goldsmith MF. HTLV-III testing of donor blood imminent; complex issues remain. JAMA 1985;
253:173-81.
3. Marwick C. Use of AIDS antibody test may provide more answers. JAMA 1985; 253:1694-9.
4. Sivak SL, Wormser GP. Predictive value of a screening test for antibodies to HTLV-III. Am J Clin
Pathol 1986; 85:700-3.
5. Ward JW, Grindon AJ, Feorino PM, Schable C, Parvin M, Allen JR. Laboratory and epidemiologic
evaluation of an enzyme immunoassay for antibodies to HTLV-III. JAMA 1986; 256:357-61.
6. Cleary PD, Barry MJ, Mayer KH, et al. Compulsory premarital screening for the human
immunodeficiency virus: technical and public health considerations. JAMA 1987;258:1757-62.
7. Schwartz JS, Dans PE, Kinosian BP. Human immunodeficiency virus test evaluation, performance,
and use: proposals to make good tests better. JAMA 1988;259:2574-9.
8. Turnock BJ, Kelly CJ. Mandatory premarital testing for human immunodeficiency virus: the Illinois
experience. JAMA 1989;261:3415-8.
9. Peterson LR, White CR, and the Premarital Screening Study Group. Premarital screening for
antibodies to human immunodeficiency virus in the United States. Am J Public Health 1990;80:1087-
1090.
9. McKilip J. The effect of mandatory premarital HIV testing on marriage: the case of Illinois. Am J
Public Health 1991;81:650-3.
11. Albritton WL, Vittinghoff E, Padian NS. Human immunodeficiency virus testing for patient-based and
population-based diagnosis. J Infect Dis 1996:174(Suppl 2):S176-81.
12. Quinn TC. Acute primary HIV infection. JAMA 1997;278:58-62.
CDC-EIS, 2003: Screening for HIV (871-703) – Student’s Guide Page 12
SUMMARY OF SCREENING TEST MEASURES
Condition
Truly Present
Condition
Truly Absent
Test positive True Positive False Positive Total Testing Positive
Test negative False Negative True Negative Total Testing Negative
Total True Prevalence 1 ! Prevalence Size of Population
Bayes Theorem Formulas for PVP and PVN:

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questions;

G Define and perform calculations of sensitivity, specificity, predictive-value positive, and
predictive-value negative;
G Describe the relationship between prevalence and predictive value;
G Discuss the trade-offs between sensitivity and specificity;
G List the principles of a good screening program.

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