cumulative incidence of false-positive test results in lung cancer screening

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Cumulative Incidence of False-Positive Test Results in LungCancer ScreeningA Randomized Trial

Jennifer M. Croswell, MD, MPH; Stuart G. Baker, ScD; Pamela M. Marcus, PhD; Jonathan D. Clapp, BS; and Barnett S. Kramer, MD, MPH

Background: Direct-to-consumer promotion of lung cancer screen-

ing has increased, especially low-dose computed tomography (CT).

However, screening exposes healthy persons to potential harms,

and cumulative false-positive rates for low-dose CT have never

been formally reported.

Objective: To quantify the cumulative risk that a person who

participated in a 1- or 2-year lung cancer screening examination

would receive at least 1 false-positive result, as well as rates of

unnecessary diagnostic procedures.

Design: Randomized, controlled trial of low-dose CT versus chest

radiography. (ClinicalTrials.gov registration number: NCT00006382)

Setting: Feasibility study for the ongoing National Lung ScreeningTrial.

Patients: Current or former smokers, aged 55 to 74 years, with a

smoking history of 30 pack-years or more and no history of lung

cancer (n 3190).

Intervention: Random assignment to low-dose CT or chest radiog-

raphy with baseline and 1 repeated annual screening; 1-year

follow-up after the final screening. Randomization was centralized

and stratified by age, sex, and study center.

Measurements: False-positive screenings, defined as a positivescreening with a completed negative work-up or 12 months ormore of follow-up with no lung cancer diagnosis.

Results: By using a KaplanMeier analysis, a persons cumulativeprobability of 1 or more false-positive low-dose CT examinationswas 21% (95% CI, 19% to 23%) after 1 screening and 33% (CI,31% to 35%) after 2. The rates for chest radiography were 9%(CI, 8% to 11%) and 15% (CI, 13% to 16%), respectively. A totalof 7% of participants with a false-positive low-dose CT examina-tion and 4% with a false-positive chest radiography had a resultinginvasive procedure.

Limitations: Screening was limited to 2 rounds. Follow-up after the

second screening was limited to 12 months. The false-negative rateis probably an underestimate.

Conclusion: Risks for false-positive results on lung cancer screeningtests are substantial after only 2 annual examinations, particularlyfor low-dose CT. Further study of resulting economic, psychosocial,and physical burdens of these methods is warranted.

Primary Funding Source: National Cancer Institute.

Ann Intern Med. 2010;152:505-512. www.annals.org

For author affiliations, see end of text.

Despite the lack of a completed randomized, controlledtrial demonstrating the efficacy of low-dose computedtomography (CT) in reducing mortality from lung cancer,its use as a screening tool is gaining increased attention inthe past several years. Some hospitals and advocacy organi-zations have actively promoted CT screening to the public.

A 2007 New York Times article quotes the director of sur-gical oncology at Greenwich Hospital, Greenwich, Con-necticut, as predicting that within the next five years, lungcancer screening will be routine, like mammography andcolonoscopy (1). One advocacy group mounted a nationalDemand a CAT Scan billboard campaign in 2008 (2).The Lung Cancer Mortality Reduction Act of 2009 Senatebill states that significant and rapid improvements in lungcancer mortality can be expected through greater use andaccess to lung cancer screening tests (3).

Utilization rates of chest radiography or CT screeningin the community setting have not been well studied. TheDutchBelgian randomized lung cancer (NELSON) (4)screening trial reported that 3.1% of participants received ascreening chest radiography or CT examination outside thetrial by 24 months after randomization (this may not berepresentative of U.S. rates). Surveys of U.S. communityphysicians have demonstrated high enthusiasm for screen-ing. One study found that two thirds of family practitio-

ners, internists, and gynecologists and 82% of general sur-geons recommended chest radiography for lung cancerscreening every 1 to 2 years (5).

However, as is the case with all medical interventions,screening tests may generate both benefits and harms. Iflung cancer screening becomes national health policy, wemust have solid evidence not only about the benefits butalso the harms of testing. This is particularly importantbecause asymptomatic persons are the target population.Major harms associated with screening include the risk foroverdiagnosisthe discovery of indolent lung cancer that

would not lead to a persons death or cancer in a person

See also:

Print

Editors Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-40

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Appendix

Appendix Tables

CME quiz

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Annals of Internal Medicine Article

www.annals.org 20 April 2010 Annals of Internal Medicine Volume 152 Number 8 505


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who would die of a competing cause first (6, 7)and therisk for false-positive results. False-positive results are im-portant because they may have negative psychological ef-fects (8, 9), affect future adherence to other preventivehealth measures (10, 11), and generate physical harms andeconomic costs from surveillance visits and confirmatoryprocedures.

Although the Lung Screening Study has reported the

total positivity rate, we have not previously examined cu-mulative false-positivity rates by using formal statisticalmethods, and the false-positive component most accuratelyrepresents a clinically important burden of screening. Wefocus on the probability of false-positive test results andresulting diagnostic procedures when chest radiographyand CT are used as early detection strategies for lungcancer.

METHODSDesign

The Lung Screening Study was a 2-year study con-

ducted by 6 centers participating in the Prostate, Lung,Colorectal, and Ovarian Cancer Screening Trial. It was afeasibility study for the ongoing National Lung ScreeningTrial (12, 13).

Setting and Participants

The Lung Screening Study had a goal of randomlyassigning 3000 participants at elevated risk for lung cancer.Enrollment was achieved through mass mailings of recruit-ment materials, along with public service announcements,posters, and physician recruitment efforts. A total of 3318persons were randomly assigned from September 2000 to

January 2001 to have chest radiography or low-dose CT.

All participants signed a consent form approved by theinstitutional review board before randomization.

Eligible participants were aged 55 to 74 years, had acigarette smoking history of 30 pack-years or more, and

were current smokers or had quit in the past 10 years.Exclusion criteria included chest CT within 24 months of

enrollment, previous lung cancer, removal of part or all ofa lung, current treatment of any cancer except nonmela-noma skin cancer, and ongoing participation in a cancerprevention or screening trial other than a smoking cessa-tion study.

Randomization and Interventions

Once eligibility was established and consent was ob-tained by a study center, participants were randomly as-signed to a treatment group through a single centralized,secure, Web-based system (which generated random code)operated by the trial coordinating center. This process en-sured allocation concealment for study site investigators.

Randomization was stratified by age group (in 5-year cat-egories), sex, and study center by using variable blocksizes. Once randomization occurred, participants andstudy investigators were not blinded to the screeningmethod received.

Two screening examinations were possible: baseline(T0) and repeated examination (T1) 1 year later. Partici-pants were eligible for the second screening if they did notreceive a diagnosis of lung cancer after the first examina-tion. For inclusion in this analysis of false-positive results,participants had to adhere to at least 1 screening.

Low-dose CT scans were obtained with the followingtechnical parameters: 120 to 140 kV peak, 60 ma, scantime of 1 s, 5-mm collimation, pitch of 2 or equivalent,and contiguous reconstructions. Chest radiography con-sisted of single posteroanterior views and was obtained byusing high-kilovolt equipment at a tube-to-receiver dis-tance of 6 to 10 feet.

Each study center had 1 or more (range, 1 to 14)board-certified radiologists interpreting the examinations.

A second radiologist blinded to the initial interpretation asa quality-control measure reread a small sample of films(n 20) at each center.

Outcomes and Follow-up

For CT, the definition of a positive screening resultchanged slightly between the T0 and T1 scans to bettermatch accumulating prognostic evidence: Noncalcifiednodules larger than 3 mm at T0 scan or 4 mm or larger atT1 scan were considered suspicious for cancer. Other ab-normalities (including spiculated noncalcified nodules ofany size; focal parenchymal opacification; endobronchiallesions; hilar, mediastinal, bony, or pleural masses; and ma-

jor atelectasis) could also be deemed positive according tothe radiologists judgment. For chest radiography, nodules

with circular opacity of 3.0 cm or less in diameter, massesgreater than 3.0 cm, hilar or mediastinal lymph node en-largement (excepting calcified nodes), major atelectasis, in-

Context

The ongoing National Lung Screening Trial aims to definethe effectiveness of screening for lung cancer. However,imaging studies to screen for lung cancer are currently

marketed to patients.

Contribution

These data from a pilot study for the National Lung

Screening Trial show a 33% cumulative incidence of false-positive results after 2 computed tomography examina-tions and 15% after 2 chest radiography examinations.

tomography and 4% for chest radiography) with false-positive results required invasive testing to determine

that the screening-detected lesion was not cancer.

Implication

Physicians and patients should bear in mind high false-

positive rates when considering screening for lung cancer

with computed tomography or chest radiography.

The Editors

Article False-Positive Test Results in Lung Cancer Screening

506 20 April 2010 Annals of Internal Medicine Volume 152 Number 8 www.annals.org

Substantial proportions of patients (7% for computed


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filtrates or consolidation, and pleural masses were consid-ered suggestive of cancer.

We defined a false-positive screening result as a posi-tive screening with a completed negative work-up orfollow-up of at least 12 months with no diagnosis of lungcancer. Because performing biopsy of all screening-

detected lung abnormalities was impractical and undesir-able (because of the potential for harm), we had to choosea definition of a false-positive test result that relied ondiagnostic work-ups for suspicious examinations. For per-sons who did not receive definitive testing, given that lungcancer as a general rule is one of the more aggressive tu-mors, we felt that a 12-month monitoring period was areasonable cutoff for a false-positive result.

We defined a false-negative examination result as anegative screening associated with a diagnosis of lung can-cer within 1 year of the examination. This definition islimited in its ability to discern between types of cancertruly missed by screening and aggressive interval tumors

that may develop between tests. Furthermore, because theLung Screening Study was a feasibility trial, follow-upof negative examination findings was not done in thesame systematic manner as for positive test results. Per-sons in whom screening was negative at T1 did notcontinue to have follow-up in the trial; reported false-negative rates are limited to the period between the T0and T1 examinations.

All positive results were communicated by telephoneand mailed to participants and their designated physician

within 3 weeks. The Lung Screening Study did not specifya diagnostic algorithm for follow-up of positive results;

centers would provide recommendations for diagnostic ac-tion if requested. Center personnel abstracted medicalrecords relating to follow-up of positive screening results.This process began after a positive screening result andcontinued until a conclusive diagnosis was made or 12months had passed. In addition, study participants com-pleted a study update form at the T1 screening to identifyany interval cases of lung cancer.

Classifications for diagnostic follow-up were dividedinto categories by author consensus: imaging examinations(noninvasive), minimally invasive procedures (bronchos-copy), moderately invasive procedures (for example, bi-

opsy, thoracentesis, video-assisted thoracoscopy), and ma-jor surgical procedures (thoracotomy or lung resections).

Statistical Analysis

Our study attempts to answer the question, What isthe probability that a person entering a lung cancer screen-ing program involving 1 or 2 screening tests will have atleast 1 false-positive CT or chest radiography? A personcould contribute to the cumulative risk curve only once,after a first false-positive test result; this avoided double-counting of suspicious nodules and artificial inflation ofthe curve. KaplanMeier analysis generated cumulative in-cidence curves based on estimated probability of a first

false-positive result at baseline or second screening received(14). For the base-case analysis, we considered persons withincomplete follow-up (12 months) after a positivescreening to have received a false-positive result. As a sen-sitivity analysis, we assumed that a proportion of persons

with insufficient follow-up after a positive examination re-

sult did have cancer, in which the proportion was esti-mated as published positive predictive values (from othertrials) of CT (7%) and chest radiography (2%) for screen-ing detection of lung cancer (15, 16).

Logistic regression was done through 2 models toidentify potential participant characteristics associated withincreased odds of a false-positive examination result afterthe first screening or the second screening (if the firstscreening was negative). Variables included age, currentversus former smoking status, and smoking history of 60pack-years or more versus 30 to 59 pack-years. We ad-

justed logistic regression analyses for screening center. Wecalculated odds ratios (ORs) separately for CT and chest

radiography. We also examined variance in the false-positive rate by study center.

Role of the Funding Source

The Lung Screening Study was performed under con-tracts awarded by the National Cancer Institute, and alldata were collected under those contracts. Most of the au-thors who designed, analyzed, and wrote this study arefederal employees.

RESULTSDemographic Characteristics

Table 1 shows demographic characteristics of thestudy population. Participants were more likely to be men(59%) and current smokers (57%). As expected, random-ization achieved balance in baseline patient characteristics.

Table 1. Demographic Characteristics

Characteristic Low-Dose CT(n 1610),n (%)

Chest Radiography(n 1580),n (%)

Age

6574 y 516 (32) 502 (32)5564 y 1094 (68) 1078 (68)

Sex

Female 675 (42) 637 (40)

Male 935 (58) 943 (60)

Smoking status

Current 929 (58) 897 (57)

Former 681 (42) 683 (43)

Smoking history

60 pack-years 673 (42) 687 (43)

3059 pack-years 937 (58) 893 (57)

CT computed tomography.

ArticleFalse-Positive Test Results in Lung Cancer Screening



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Adherence Rates

A total of 1610 participants underwent at least 1 CT,and 1580 participants underwent at least 1 chest radiogra-phy (Figure 1). A total of 1374 participants in the CTgroup (97%) and 1287 participants in the chest radiogra-phy group (95.2%) received both examinations. Adherence

was lower in both groups for the second screening than forthe baseline test.

False-Positive and False-Negative Results

A total of 31% (n 506) of participants in the CTgroup and 14% (n 216) of participants in the chestradiography group received at least 1 false-positive result.

In comparison, screening CT was true-positive in 38 in-stances (2% of participants) and chest radiography wastrue-positive in 16 instances (1% of participants).

Figure 2 illustrates the cumulative risk that a personwould receive at least 1 false-positive result in a lung cancerscreening program over several years. At baseline screening,the risk for a false-positive result is 21% (95% CI, 19% to23%) for CT and 9% (CI, 8% to 11%) for chest radiog-raphy. These risks increase to 33% (CI, 31% to 35%) and15% (CI, 13% to 16%), respectively, at second examina-tion. Sensitivity analysis, which assumed that 7% of par-ticipants in the CT group and 2% of participants in the

chest radiography group with insufficient follow-up after apositive screening had true-positive results, yielded identi-cal rates. Four examinations with false-negative results werereported between the baseline and T1 examinations. All

were in the chest radiography group (0.2% of participantsin this group).

Diagnostic Follow-up and Invasive Procedures

Table 2 shows absolute rates of diagnostic follow-upby category. Of persons with at least 1 false-positive CT orchest radiography, 61% (n 308) and 51% (n 110),respectively, received 1 or more secondary imaging tests.The overall percentage of participants who had at least 1

invasive procedure as a result of a false-positive result was7% for CT and 4% for chest radiography. Bronchoscopieswere the most common invasive procedure resulting fromfalse-positive CT (5% of participants with a false-positiveresult). The proportion of participants who had a moder-ately invasive procedure was 4% for false-positive CT and3% for false-positive chest radiography. Rates of partici-pants who had major surgical procedures for benign disease

were similar (2%), although absolute numbers differedby a factor of 2 (8 CT recipients and 4 chest radiographyrecipients).

Participant Characteristics and False-Positive Risk

We did multivariable analyses to investigate poten-tial participant characteristics associated with increasedodds of a false-positive result after first or second screen-ing received (in which the first screening was negative).Our models included age (65 to 74 years vs. 55 to 64years), smoking status (current vs. former), smoking his-tory (60 pack-years vs. 30 to 59 pack-years), andstudy center.

First Screening Received

For CT, older versus younger age demonstrated anonstatistically significant trend toward increased odds of

Figure 1. Study flow diagram.

Mailings (n = 653 417)

Contacted screening center

(n = 12 270)

Allocated to low-dose CT

(n = 1660)

Received T0 screening: 1586

Did not receive T0

screening: 74


Did not receive T1

screening: 262

Allocated to chest radiography

(n = 1658)


Did not receive T0

screening: 108


Did not receive T1

screening: 341

Assessed for eligibility

(n = 4828)

Randomly assigned (n = 3318)

Excluded (n = 1510)

Spiral CT in past 2 y: 148

Did not consent: 1362*

T0 screening (n = 1586)

Sufficient follow-up: 1580

Insufficient follow-up: 6










Analyzed (n

= 1610)Excluded from analysis: missed

or declined all screenings

(n = 50)

Analyzed (n

= 1580)Excluded from analysis: missed

or declined all screenings

(n = 78)

CT computed tomography.* There was a lag between eligibility assessment and randomization ateach center. Once the target sample size (n 3000) was reached, persons

who were eligible but had not yet consented were not randomly assignedunless they had already been invited to participate. Sufficient follow-up means that a person had a negative screeningresult, 12 months of documented follow-up after a positive screeningresult, or a completed diagnostic work-up after a positive screening ex-amination. For the base-case analysis, persons with insufficient follow-upafter a positive examination were included in the analysis but were as-sumed to have received a false-positive test result.




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a false-positive screening result (OR, 1.28 [CI, 0.98 to1.67]). This effect was not seen in the chest radiographygroup (OR, 1.11 [CI, 0.77 to 1.60]). Current versusformer smoking status did not show an association withfalse-positive results (OR, 1.15 [CI, 0.88 to 1.49] forCT and 1.31 [CI, 0.92 to 1.88] for chest radiography).

Greater number of pack-years smoked was not associ-ated with increased odds of a false-positive result (OR,0.92 [CI, 0.71 to 1.19] for CT and 1.02 [CI, 0.72 to1.45] for chest radiography).

The estimated probability of a false-positive result onthe first screening received varied by center. For the com-bined categories of age (65 to 74 years), current smoker,and smoking history of 60 pack-years or more, the estimatefor CT varied from 10% to 42% across centers. For chestradiography, the estimated false-positive rate for the com-bined categories of age (65 to 74 years), current smoker,and smoking history of 60 pack-years or more varied from3% to 19% across centers. The Appendix (available at www

.annals.org) provides further details.

Second Screening Received

Older versus younger age was not associated withodds of false-positive CT (OR, 1.20 [CI, 0.83 to 1.74])but was associated with twice the odds of false-positivechest radiography (OR, 2.03 [CI, 1.23 to 3.36]). Cur-rent versus former smoking status was not associated

with odds of false-positive CT (OR, 1.07 [CI, 0.75 to1.52]) or chest radiography (OR, 0.85 [CI, 0.51 to1.40]). More pack-years of smoking was associated with1.5 times increased odds of a false-positive result for CT

(OR, 1.53 [CI, 1.08 to 2.18]), but this was not observed inthe chest radiography group (OR, 1.12 [CI, 0.68 to 1.85]).

DISCUSSIONTo our knowledge, our study is the first to formally

evaluate a persons cumulative risk for receiving at least 1

false-positive test result in a program of low-dose CTscreening for lung cancer over several years. The probabil-

ity of a false-positive result is substantial after 2 annualexaminations (33%). Of participants with a false-positiveCT scan, 7% had an unnecessary invasive procedure and2% had major surgery for benign disease.

Cumulative false-positive rates associated with screen-ing tests have been infrequently reported; most studies ofthis nature have focused on mammography (1720). An

Figure 2. Cumulative probability (95% CI) of a false-positive

result for a person who participated in a lung cancer

screening program over several years.

CumulativeProbability

ofa

False-PositiveResult,

%

Screening Test

21%

(19%23%)

Low-dose CT

Chest radiography

9%

(8%11%)

15%

(13%16%)

33%(31%35%)

Participants at risk, n

Low-dose CT 1610 1114

Chest radiography 1580 1183

0 1 2

0

5

10

15

20

25

30

3540

45

50

The cumulative probability is for the first false-positive result receivedfrom a number of tests done. Participants at risk for screening test 1 isthe number of participants who received at least 1 screening test (at T0if both T0 and T1 screenings were taken or at T1 if T0 screening wasmissed). Participants at risk for screening test 2 is the number of partic-ipants who received both tests (at T0 and T1) in whom the result of thefirst test received was negative. See the Appendix (available at www.annals.org) for more detailed information. CT computed tomogra-phy.

Table 2. Rates of False-Positive Results That Prompted Diagnostic Follow-up*

Procedure Type Low-Dose CT (n 506) Chest Radiography (n 216)

Participants,n False-PositiveResults, % Participants,n False-PositiveResults, %

Imaging examinations 308 61 110 51

Minimally invasive procedure 25 5 6 3

Moderately invasive procedure 20 4 7 3

Major surgical procedure 8 2 4 2

Any invasive procedure 33 7 9 4

CT computed tomography.* Approximately 3% of all participants with a positive screening result received no diagnostic follow-up. Total number of persons with at least 1 false-positive result in each group. A person could contribute only once to each category, even if he or she had more than 1false-positive result. Bronchoscopy. Procedures included lung biopsy (any method except open surgery), lymph node biopsy, mediastinoscopy, mediastinotomy, thoracentesis, and video-assisted thoracoscopy. Procedures included lung resection and thoracotomy. Any invasive procedure describes the number and percentage of participants who received at least 1 minimally invasive, moderately invasive, or major surgical procedure.A person could contribute to this group only once, regardless of the number of procedures he or she had. Imaging examinations were not considered invasive procedures.




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estimate of the cumulative false-positive rate for chest ra-diography in lung cancer screening as part of a larger eval-uation of false-positive rates in screening programs thatused multiple testing methods was about 14% after 2screenings and 22% after 4 screenings, which aligns withour findings (21). Previous studies have generally reported

discovery rates of all noncalcified nodules in persons whohad CT screening. These rates have varied widely, depend-ing on screening frequency and other factors; the averagerange is 25% to 50% of participants (16, 22).

Clinical experience suggests that, in general, the largerthe nodule, the greater the suspicion that the lesion is or

will become cancerous (23). Despite this rule of thumb, nouniform consensus on how best to categorize and managelesions detected on CT exists. Several studies of CT forlung cancer screening used protocols that called for diag-nostic follow-up of varying intensity for all detected nod-ules (2429), although most lesions detected by low-doseCT are smaller than 4 mm (30). Fleischner Society guide-

lines for management of incidental nodules detected onnonscreening CT suggest that lesions smaller than 4 mmpose minimal risk, and as such, generally recommend nofurther follow-up for low-risk patients and a single re-peated screening at 12 months for high-risk patients withno intervention if the lesion is unchanged (31). The defi-nition of a positive test result used in the Lung ScreeningStudy (3 mm or 4 mm, depending on year) attempted torule out lesions that were least likely to be indicative ofcancer; the study design sought to minimize the number offalse-positive results. The relatively high cumulative risk fora false-positive result after 2 examinations may represent a

conservative estimate of rates in community practice, inwhich all nodules, regardless of size, may be more likely toreceive follow-up.

Multislice scanners were emerging at the time of theLung Screening Study, and some, but perhaps not all, ofthe study sites had 4-row scanners in use. It is not known

what the effect of single versus multirow detectors wouldbe on false-positive rates, nor the effect of additional (forexample, 16 or 64) slices.

Previous studies have reported on surgery rates for be-nign disease; the proportion of persons with a screening-detected nonmalignant lesion who had surgery has rangedfrom about 0.6% to 2.7% for CT (2628, 3235). This isconsistent with our findings.

More than half of participants with false-positive chestradiography or CT had at least 1 additional imaging exam-inationsome at higher radiation doses than that of theoriginal testwhich exposed these persons to a theoreticalrisk for radiation-induced carcinogenesis. This is poten-tially concerning in the target population because currentevidence indicates that radiation and smoking damage in-teract synergistically, and the interaction is near multipli-cative (36, 37). Consensus has not been reached on a singlediagnostic algorithm for positive screening examinations;however, repeated scans (of varying dose) at 1, 3, 6, 12,

and/or 24 months have been advocated (2329, 38). Al-though no long-term longitudinal data on the effects ofcumulative radiation exposure are available, estimates ofcancer risks have been done by using relevant data fromcohort studies of survivors of long-term atomic bomb ex-posure (39, 40). One estimate found that among female

smokers aged 60 years, a series of 3 low-dose chest CTswould generate an excess lung cancer risk for about 1.5women per 1000 exposed (39). The National Lung Screen-ing Trial is collecting information on cumulative radiationexposure among participants and should help clarify thisimportant issue.

Negative psychological consequences of false-positivescreening are also of concern. Although data for lung cancerscreening are limited, 1 study examining the effect of CT onquality of life found that about half of participants had dis-comfort and dread while waiting for confirmation of screen-ing results (41). Because positive lung cancer screening results

may encompass diagnostic uncertainty for up to 24 months,further investigation of the long-term psychological effects offalse-positive test results would be important.

A high rate of false-positive test results may place eco-nomic burdens on persons and the health care system. Onestudy that investigated medical care expenditures triggered byfalse-positive test results found that the adjusted mean differ-ence in spending after such a test was an additional $1024 fora woman and $1171 for a man in 1 year (42). Because 31% ofparticipants in the CT group received at least 1 false-positiveresult in 2 years, the effect these rates could have on the cost-effectiveness of CT (if proven effective) is apparent.

Our study has several limitations. As with all cancerscreening trials, a healthy volunteer effect is likely to bepresent. This effect has been documented in the Prostate,Lung, Colorectal, and Ovarian Cancer Screening Trial,

which includes study centers that participated in the LungScreening Study (43).

The Lung Screening Study was a pilot study and, assuch, was limited to 2 rounds of screening and 1 year offollow-up after the last examination. Although it is possiblethat this study might overestimate the cumulative risk for afalse-positive result, it is unlikely that a large proportion offalse-positive results would convert to diagnoses of cancer.

A small proportion (0.04% for each method) of Lung

Screening Study participants was lost to follow-up afterpositive examination findings; this studys baseline assump-tion was that those findings were false positive. Becausethis could potentially overestimate the cumulative false-positive risk, a sensitivity analysis was done; however, thecumulative risk estimates remained unchanged.

Because the Lung Screening Study was a feasibility trial,negative screening results were not systematically followed inthe same manner as positive screening results. Recording offalse-negative results was limited to the period between the T0and T1 examinations, and the estimated false-negative rate iscrude and probably an underestimate.




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The analysis of associations between patient character-istics and false-positive risk should be considered explor-atory. The Lung Screening Study had a relatively modestsample size; subgroup populations were small; and, as inany multivariable analysis, multiplicity potentially inflatedthe probability of a type I error. The variation in estimated

false-positive rates by center is probably due to the effectsof interobserver variability in the assessment of a positiveexamination among centers. Studies of interobserver agree-ment on interpretation of chest CT scans have demon-strated notable variations among readers (4446). Semi-automated volumetric determinations of nodule size orcomputer-aided detection programs have been proposed asmethods that could theoretically reduce observer variabil-ity, although the ultimate degree of effect this might haveon false-positive rates is unknown.

Given the relatively high probability of a false-positivelow-dose CT lung cancer screening examination, it is im-portant that providers have careful discussions with pa-

tients who request this technology to help them weighknown harms against currently theoretical benefits. Furtherinvestigation into the physical, psychological, and eco-nomic ramifications of false-positive low-dose CT screen-ing test results is warranted.

From National Institutes of Health, National Cancer Institute, Bethesda,and Information Management Services, Rockville, Maryland.

Portions of this work were presented at the annual meeting of the Amer-ican Society of Clinical Oncology, Orlando, Florida, 29 May2 June2009 (Abstract 1502).

Disclaimer: The views expressed in this article are those of the authorsand do not necessarily represent the views of the U.S. federal governmentor the National Institutes of Health.

Acknowledgment: The authors thank all participants in the LungScreening Study and the centers and health professionals involved in thistrial. They also thank Dr. Phil Prorok, Dr. Christine Berg, the NationalLung Screening Trial Executive Committee, and Dr. Thomas Louis fortheir helpful input during study development.

Grant Support: The Lung Screening Study was funded by the NationalCancer Institute; no monies or grants were awarded to any of the authorsto perform this study.

Potential Conflicts of Interest: Dr. Croswell: Financial relationshipsinvolving spouse: Husband owns shares in Johnson & Johnson.Dr. Kramer: Money received: Journal of the National Cancer Institute.Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNumM09-1802.

Reproducible Research Statement: Study protocol: Available at http://prevention.cancer.gov/programs-resources/groups/ed/programs/lss/manual.Statistical code: Written in Mathematica 7.0 (Wolfram Research, Cham-paign, Illinois) and available by written request to Dr. Baker (e-mail,[email protected]). Data set: Available by written request (to includethe readers objectives and the specific data required) to Dr. Baker (e-mail, [email protected]).

Requests for Single Reprints: Jennifer M. Croswell, MD, MPH, Officeof Medical Applications of Research, National Institutes of Health,6100 Executive Boulevard, Suite 2B-03, Bethesda, MD 20892; e-mail,[email protected].

Current author addresses and author contributions are available at www.annals.org.

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Current Author Addresses: Dr. Croswell: Office of Medical Applica-

tions of Research, National Institutes of Health, 6100 Executive Boule-vard, Suite 2B-03, Bethesda, MD 20892.

Dr. Baker: Biometry Research Group, Division of Cancer Prevention,

National Cancer Institute, EPN 3131, 6130 Executive Boulevard, Be-thesda, MD 20892-7354.

Dr. Marcus: Division of Cancer Prevention, National Cancer Institute,

6130 Executive Boulevard, Suite 3131, Bethesda, MD 20892-7354.

Mr. Clapp: Information Management Services, 6110 Executive Boule-vard, Suite 310, Rockville, MD 20852.

Dr. Kramer: Office of Disease Prevention, National Institutes of Health,

6100 Executive Boulevard, Suite 2B-03, Bethesda, MD 20892.

Author Contributions: Conception and design: J.M. Croswell, B.S.

Kramer.Analysis and interpretation of the data: J.M. Croswell, S.G. Baker, B.S.

Kramer, J.D. Clapp.

Drafting of the article: J.M. Croswell, B.S. Kramer.

Critical revision of the article for important intellectual content: J.M.Croswell, S.G. Baker, P.M. Marcus, B.S. Kramer.

Final approval of the article: J.M. Croswell, S.G. Baker, P.M. Marcus,

B.S. Kramer.Statistical expertise: S.G. Baker.

Collection and assembly of data: J.M. Croswell, P.M. Marcus, J.D.

Clapp.

APPENDIXThis appendix describes the statistical calculations in more

detail.

Summary of the DataThe possible outcomes were coded as 0, indicating no false-

positive result (no FP); 1, indicating a false-positive result (FP);

2, indicating that the test was missing (missing); or 3, indicating

a positive test result with insufficient follow-up (PWIF) (Appen-

dix Table 1).

The count data are summarized in Appendix Tables 1 to 9.

Formulas for Computing Estimate False-Positive RatesLet xij denote a number with outcome i at round T0 and

outcome jat round T1, for a particular screening method, either

chest radiography or low-dose CT. These are the numbers in the

cells ofAppendix Table 1. Let xiP xi0 xi1 xi2 xi3 denote

the row sums.

We let fdenote the probability that a person who received a

positive result on screening with insufficient follow-up had a

true-positive result (that is, has disease). Under the base case, we

set f 0. Under the sensitivity analysis, we set f 0.02 for chest

radiography and f 0.07 for low-dose CT. The estimate of f,

which comes from other studies, is the probability of disease

given a positive screening test result, which is called the positive

predictive value. One minus the positive predictive value is the

probability of no disease given a positive screening test result.

Our formulas are as follows.

For a first screening at T0:

y1a number with a first FP at T0 x1P x32 (1 f)

n1a number at risk for first FP at T0 x0P x1P x32

For a first screening FP at T1 because of missing at T0:

y1b number with a first FP at T1 x21 x23 (1 f)

n1b number at risk for first FP at T1 x20 x21 x23

We can then write:

y1 y1a y1b number with a first FP

n1 n1a n1b number at risk for a first FP

For a second screening at T1 after no FP at T0:

y2 number with FP at T1 x01 x03 (1 f)

n2 number at risk for FP at T1 x00 x01 x03

From the above quantities, we computed:

h1 hazard for first FP h1 y1/n1h2 hazard for FP after FP 0 h2 y2/n2

The estimated probability of no FPs on 2 screenings is

S (1 h1) (1 h2).

Therefore the estimated probability of at least one FP on 2

screenings is P 1 S.

From the binomial distribution, var(hj) hj (1 hj)/nj . By

using the delta method,var(P) var(S) S2 var(log(S)), in which

var(log(S)) var(h1)/(1 h1)2 var(h2)/(1 h2)

2,

x1/[n1 (n1 x1)] x2/[n2 (n2 x2)], which is the Green-

wood formula.

Computed False-Positive RatesFor low-dose CT, using the formulas and data cells de-

scribed, h1 335/1610 0.21. This is the estimated probability

of a false-positive result on the first screening received. h2

171/114 0.15; this is the estimated probability of a false-

positive result on the second screening received, given that the

first result was negative. The cumulative probability of a false-positive result is therefore h1 (0.21) for the first test received and

1 (1 h1)(1 h2) 1 (1 0.21)(1 0.15) 0.33 for the

second test received.

For chest radiography, h1 147/1580 0.09. This is the

estimated probability of a false-positive result on the first screen-

ing received. h2 69/1183 0.06; this is the estimated proba-

bility of a false-positive result on the second screening received,

given that the first result was negative. The cumulative probabil-

ity of a false-positive result is therefore h1 (0.09) for the first test

received and 1 (1 h1)(1 h2) 1 (1 0.09)(1 0.06)

0.15 for the second test received.

Logistic Regression ModelFor each screening method, we fit the following logistic re-

gression models:

logit[pr(FP on first screening received)]

age I(age) smoker I(smoker) i Ci I(center i) pyI(pack-years),

logit[pr(FP on second screening received after no FP on first

screening received)]

age I(age) smoker I(smoker) i Ci I(center i) pyI(pack-years),

in which

I(smoker) 1 if current smoker, and 0 if former smoker,

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I(age) 1 age is between 65 and 74, and 0 if age is between

55 and 64,

I(center i) 1 if from center I, and 0 otherwise,

I(pack years) 1 if pack-years is 60 or more, and 0 if less

than 60.

Recoding Data for Fitting Logistic Regression Models

Before fitting the logistic regressions we recoded the original

data as follows. We assumed the base case in which a PWIF is an

FP. We denote the original pair of data by {outcome at T0,

outcome at T1}, in which 0 indicated no false-positive result (no

FP), 1 indicated a false-positive result (FP), 2 indicated a missing

test, and 3 indicated a positive result with insufficient follow-up

(PWIF).

We recoded the original pair as a new pair, {outcome for

first screening received and outcome for second screening re-

ceived after no FP on first screening}, in which 0 indicated no

false-positive result (no FP), 1 indicated a false-positive result

(FP), and 2 indicated information outside of the risk set.The rules for recoding were as follows.

If the outcome at T0 in the original pair was 0 (no FP), then

the outcome of the new pair was identical to that for the original

pair, except that PWIF was coded as FP under the base case.

If original pair {0, 0}, then new pair {0, 0}




If the outcome at T0 in the original pair was 1(FP), then the

outcome of the new pair was coded as {1, 2} because the outcome

at the second screening is not in the risk set.




If original pair {1, 3}, then new pair {1, 2}If the outcome at T0 in the original pair was 2 (missing),

then the outcome of the new pair was coded as {outcome at T1,

2} because the screening at T1 is now the first screening, and the

second screening is not in the risk set. Also PWIF was coded as

FP under the base case.





If the outcome at T0 in the original pair was 3 (PWIF), then

the outcome of the new pair was coded as {1, 2} because PWIF is

coded as 1(FP) under the base case, and the second screening isnot in the risk set.





Appendix Table 1. Count Data for Outcomes of Screening

Outcome of Testat T0

Outcome of Test at T1

0 (No FP) 1 (FP) 2 (Missing) 3 (PWIF)

Low-dose CT

0 (no FP) 943 159 144 12

1 (FP) 86 157 62 17

2 (Missing) 17 7 50 0

3 (PWIF) 0 0 6 0

Chest radiography

0 (no FP) 1114 66 222 3

1 (FP) 69 24 36 11

2 (Missing) 28 2 78 0

3 (PWIF) 0 0 5 0

CT computed tomography; FP false-positive result; missing missing test;no FP no false-positive result; PWIF positive test result with insufficientfollow-up.

Appendix Table 2. Parameter Estimates (SE) for the Logistic

Regression Model for the False-Positive Rate on First

Screening Received

Variable Parameter Estimate (SE)

Low-Dose CT(n 1160)

Chest Radiography(n 1580)

age (aged 6574 y) 0.25 0.14 0.11 0.019

smoker (current smoker) 0.14 0.13 0.27 0.18

Center 1 0.77 0.19 1.85 0.26

Center 2 2.51 0.23 2.44 0.25

Center 3 2.25 0.23 2.86 0.30

Center 4 0.61 0.17 2.22 0.24

Center 5 1.26 0.18 4.04 0.48

Center 6 1.94 0.19 2.42 0.24

py (60 pack-years) 0.08 0.13 0.02 0.18


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Appendix Table 3. Odds Ratio (95% CI) for the Effect of

Age, Smoking Status, and Smoking History on the

False-Positive Rate on First Screening Received, Based on

Logistic Regression Model*

Variable Odds Ratio (95% CI)*

Low-Dose CT(n 1160)


Age

6574 y 1.28 (0.981.67) 1.11 (0.771.60)

5564 y 1.0 1.0

Smoking status

Current 1.15 (0.881.49) 1.31 (0.921.88)

Former 1.0 1.0

Smoking history

60 pack-years 0.92 (0.711.19) 1.02 (0.721.45)

3059 pack-years 1.0 1.0


* Estimates are adjusted for center.

Appendix Table 4. Estimated False-Positive Rate on First Screening Received for Low-Dose Computed Tomography, Based on

Logistic Regression Model*

Center 0, 0, 0 0, 0, P 0, S, 0 0, S, P A, 0, 0 A, 0, P A, S, 0 A, S, P

1 0.32 0.30 0.35 0.33 0.37 0.35 0.40 0.39

2 0.08 0.07 0.09 0.08 0.09 0.09 0.11 0.10

3 0.10 0.09 0.11 0.10 0.12 0.11 0.13 0.12

4 0.10 0.09 0.11 0.10 0.12 0.11 0.13 0.12

5 0.22 0.21 0.25 0.23 0.27 0.25 0.30 0.28

6 0.13 0.12 0.14 0.13 0.16 0.15 0.17 0.16

* A means I(age) 1; S means I(smoker) 1; P means I(pack-years of smoking) 1. Analysis based on 1160 participants who received at least 1 computed tomographyexamination.

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Appendix Table 5. Estimated False-Positive Rate on First Screening Received for Chest Radiography, Based on Logistic Regression

Model*

Center 0, 0, 0 0, 0, P 0, S, 0 0, S, P A, 0, 0 A, 0, P A, S, 0 A, S, P

1 0.14 0.14 0.17 0.17 0.15 0.15 0.19 0.19

2 0.08 0.08 0.10 0.10 0.09 0.09 0.11 0.12

3 0.05 0.06 0.07 0.07 0.06 0.06 0.08 0.084 0.10 0.10 0.13 0.13 0.11 0.11 0.14 0.14

5 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.03

6 0.08 0.08 0.10 0.11 0.09 0.09 0.11 0.12

* A means I(age) 1; S means I(smoker) 1; P means I(pack-years of smoking) 1. Analysis based on 1580 participants who received at least 1 chest radiographyexamination.

Appendix Table 6. Parameter Estimates (SE) for the Logistic

Regression Model for the False-Positive Rate on Second

Screening Received*

Variable Parameter Estimate (SE)

Low-Dose CT(n 1114)


age (aged 6574 y) 0.18 0.019 0.71 0.26

smoker (current smoker) 0.07 0.18 0.17 0.26

Center 1 0.47 0.25 2.99 0.48

Center 2 2.75 0.28 3.69 0.45

Center 3 3.02 0.33 3.29 0.42

Center 4 1.38 0.25 2.05 0.29

Center 5 1.59 0.24 3.34 0.41

Center 6 2.76 0.29 3.30 0.38

py (60 pack-years) 0.43 0.18 0.11 0.26

CT computed tomography.* When baseline examination was negative.

Appendix Table 7. Odds Ratio for the Effect of Age and

Smoking Status on False-Positive Rate on Second Screening

Received*

Variable Odds Ratio (95% CI)

Low-Dose CT

(n 1114)

Chest Radiography

(n 1183)

Age

6574 y 1.20 (0.831.74) 2.03 (1.233.36)

5564 y 1.0 1.0

Smoking status

Current 1.07 (0.751.52) 0.85 (0.511.40)

Former 1.0 1.0

Smoking history

60 pack-years 1.53 (1.082.18) 1.12 (0.681.85)

3059 pack-years 1.0 1.0

CT computed tomography.* When baseline examination was negative. Estimates adjusted for center.

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Appendix Table 8. Marginal Counts, Crude Rates (FP

Probabilities), and Crude ORs for Each Variable Included in

Appendix Table 3

Variable, by FPResult

Low-Dose CT(n 1610)


FP 0 FP 1 Total FP 0 FP 1 Total

Age

6574 y 393 123* 516 452 50 502

5564 y 882 212 1094 981 97 1078

SmokingCurrent 724 205 929 804 93 897

Former 551 130** 681 629 54 683

Smoking history

60 pack-years 535 138 673 623 64 687

3059 pack-years 740 197 937 810 83 893

CT computed tomography; FP false-positive; OR odds ratio.* Probability of FP if aged 6574 y 0.24; crude OR 1.30. Probability of FP if aged 6574 y 0.10; crude OR 1.12.

Probability of FP if aged 5564 y 0.19. Probability of FP if aged 5564 y 0.09. Probability of FP if current smoker 0.22; crude OR 1.20. Probability of FP if current smoker 0.10; crude OR 1.35.** Probability of FP if former smoker 0.19. Probability of FP if former smoker 0.08. Probability of FP if60 pack-years 0.21; crude OR 0.97. Probability of FP if60 pack-years 0.09; crude OR 1.00. Probability of FP if 3059 pack-years 0.21. Probability of FP if 3059 pack-years 0.09.

Appendix Table 9. Marginal Counts, Crude Rates (FP

Probabilities), and Crude ORs for Each Variable Included in

Appendix Table 7

Variable, by FPResult

Low-Dose CT(n 1114)


FP 0 FP 1 Total FP 0 FP 1 Total

Age6574 y 271 61* 332 328 31 359

5564 y 672 110 782 786 38 824

Smoking

Current 522 98 620 619 34 653

Former 421 73** 494 495 35 530

Smoking history

60 pack-years 372 83 455 482 32 514

3059 pack-years 571 88 659 632 37 669

CT computed tomography; FP false-positive; OR odds ratio.* Probability of FP if aged 6574 y 0.18; crude OR1.38. Probability of FP if aged 6574 y 0.09; crude OR 1.95. Probability of FP if aged 5564 y 0.14. Probability of FP if aged 5564 y 0.05. Probability of FP if current smoker 0.16; crude OR 1.08. Probability of FP if current smoker 0.05; crude OR 0.78.** Probability of FP if former smoker 0.15. Probability of FP if former smoker 0.07. Probability of FP if60 pack-years 0.18; crude OR 1.45. Probability of FP if60 pack-years 0.06; crude OR 1.13. Probability of FP if 3059 pack-years 0.13. Probability of FP if 3059 pack-years 0.06.

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