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Appendix A. False Negatives and False Negative Rates (FNRs): A Review

The literature cites an astounding range of laboratory FNRs, from less than 1% to 93%. In some studies, however, the reported FNR was actually the percentage of negative smears found to be positive or abnormal on review. In other studies, false-negative cases were based on a review diagnosis of ACUS rather than SIL when the initial diagnosis was negative; although the former is often used for a laboratory's internal review, only the latter is appropriately used for external evaluation of a laboratory. In addition, although an accurate laboratory FNR is based on random rescreening of a laboratory's cases, some published Pap smear rescreening studies focused on specimens collected from patients at high risk for developing cervical cancer or patients who were subsequently clinically diagnosed with SIL or carcinoma. Any reported laboratory FNR must be analyzed carefully to determine whether the value was accurately determined (Table_2).
Table_2
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TABLE 2. Study results on rescreening of Pap smears initially diagnosed as negative
===========================================================================================================================================================================
Reference                       Setting                    No. of Pap smears   Description of samples*          Threshold+           Smears found to be   False negative
                                                              rescreened                                                             false negative            rate
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Yobs et al. (16 )               2 University- based             19,474         Consecutive smears,excluding     SIL                   2.0%                      30%
                                medical centers                                cases with original diagnosis
                                                                               of unsatisfactory or diagnoses
                                                                               associated with glandular
                                                                               abnormalities
Allen et al. (17 )              2 University teaching               80         Smears from patients who had     SIL ACUS              7.5% 15.0% 17.5%
                                hospital laboratories                          had all negative smears within   Unsatisfactory
                                                                               5 years of diagnosis of high-
                                                                               grade SIL or carcinoma
Sherman & Kelly (18 )           University teaching                 123        All available smears from 20     SIL ACUS             22.7% 52.7% 66.7%
                                hospital laboratory                            women with >=3 negative smears   Unsatisfactory
                                                                               preceding a diagnosis of high-
                                                                               grade SIL or carcinoma
Nick et al. (19 )               University teaching                 351        All available negative smears    Unsatisfactory       70.7%
                                hospital laboratory                            from 143 women within 5 years
                                                                               of diagnosis of high-grade SIL
Gatscha et al. (20 )            University teaching               3,962        From 1 year,random sample and    Not stated             0.28%
                                hospital                                       targeted rescreen of smears of
                                                                               high-risk patients
                                                                    422        All available smears in the 5    ACUS                 25.8% 28.7%
                                                                               years preceding histologically   Unsatisfactory
                                                                               confirmed high-grade SIL or
                                                                               carcinoma
Tabbara & Sidawy (21 )          University teaching               2,124        Random sample; rescreening was   ACUS                  0.2%                      1.6%
                                laboratory                                     performed by a cytopathology
                                                                               fellow
Slagel et al. (22 )             University laboratory               435        Consecutive smears from a high-  SIL ACUS              0.7%  3.4%             9.4% 25.0%
                                                                               risk patient population;
                                                                               automation- assisted
                                                                               rescreening
Dean (23 )                      Teaching laboratory                            All available negative smears    Unsatisfactory       18%-29%
                                                                               in the 5 years preceding
                                                                               diagnosis of high-grade SIL or
                                                                               carcinoma
Hatem & Wilbur (24 )            2 Teaching centers                   17        Smears from patients who had     SIL ACUS             64.7% 94.1%
                                                                               had a negative smear in the 2
                                                                               years preceding a diagnosis of
                                                                               high-grade SIL or carcinoma
Wang (25 )                      Community hospital                 ~200        Combination of random smears     SIL                   3.4%
                                laboratory                                     and smears in the 5 years
                                                                               preceding a cytologic
                                                                               diagnosis of high-grade SIL or
                                                                               carcinoma
                                                                 19,623        Both random samples and          SIL                    0.48%
                                                                               consecutive smears
Personal communication,SE Wang  Community hospital                             All smears from 1 year           SIL                                           <12.5%
to ML Nielsen                   laboratory
Krieger & Naryshkin (10 )       Community hospital                             Quarterly random sampling        ACUS                 0%-17%
Inhorn & Shalkham (26 )         State laboratory                               Random sample from 1 year        ACUS                  0.7%                  9.0%-11.7%&
                                                                               All smears from 1 year from a    ACUS                  1.5%
                                                                               high-risk patient population
                                                                               All available smears in the 5    ACUS                 13.6%
                                                                               years preceding cytologic
                                                                               diagnosis of high-grade SIL or
                                                                               carcinoma
Colgan et al. (27 )             Independent laboratory            3,477        Consecutive smears               SIL ACUS              0.4%  2.4%               12.7%
Krieger & Naryshkin (10 )       Independent laboratory        >=1,000,000      Random sample from 15 years      ACUS                 0.3%-0.7%&               4%-11%
Jones (28 )                     312 Laboratories                  3,762        From responding laboratories                          SIL ACUS               10.1% 19.9%
           Unsatisfactory            20.4%
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------
* All smears rescreened were initially diagnosed as negative.
+ A false-negative cytology smear is identified when positive cells are found on rescreening of a smear initially reported to be negative. For external review, a minimum
  diagnosis of squamous intraepithelial lesions (SIL) on rescreening serves as the threshold for identifying a false negative. For a laboratory's internal review, the
  threshold is often set at atypical cells of undetermined significance (ACUS). The ACUS threshold includes SIL false negatives, and the Unsatisfactory
  threshold includes ACUS and SIL thresholds.
& Approximated study data.
===========================================================================================================================================================================

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