Hologic ThinPrep Operator's Manual
ThinPrep® Imaging System
Review Scope
Operator’s Manual
HOLOGIC, INC.
250 C
AMPUS DRIVE
MARLBOROUGH, MA 01752 USA
T
EL: 1-800-442-9892
1-508-263-2900
F
AX: 1-508-229-2795
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EB: WWW.HOLOGIC.COM
For Use With Version 6.x.y Software
MAN-03352-001
The ThinPrep® Imaging System is a PC-based and automated review system for use with ThinPrep.
.
cervical cytology sample slides. The ThinPrep
Imaging System is intended to help a cytotechnologist
or pathologist highlight areas of a slide for further manual review. The Product is not a replacement
for manual review. Determination of slide adequacy and patient diagnosis is at the sole discretion of
.
the cytotechnologists and pathologists trained by Hologic to evaluate ThinPrep
and only if it is finally determined by a court of competent jurisdiction that the Product sold to Cus
prepared slides. If
tomer thereunder was defective in design or contained a manufacturing defect and that such defect
was solely responsible for an error in diagnosis that caused harm to a patient, Hologic shall indem
nify Customer for the compensatory damages paid by Customer to discharge the personal injury
judgment with respect to Product.
Caution: Federal law restricts this device to sale by or on the order of a physician, or any other practitioner licensed by the law of the State in which the practitioner practices to use or order the use of
the device and are trained and experienced in the use of the ThinPrep Imaging System.
© Hologic, Inc., 2017. All rights reserved. No part of this publication may be reproduced, transmitted, transcribed, stored in a retrieval system, or translated into any language or computer language,
in any form, or by any means, electronic, mechanical, magnetic, optical, chemical, manual, or other
wise, without the prior written permission of Hologic, 250 Campus Drive, Marlborough, Massachusetts, 01752, United States of America.
Although this guide has been prepared with every precaution to ensure accuracy, Hologic assumes no
liability for any errors or omissions, nor for any damages resulting from the application or use of this
information.
This product may be covered by one or more U.S. patents identified at
http://www.hologic.com/patentinformation/
Hologic, PreservCyt and ThinPrep are registered trademarks in the United States and other countries. All other trademarks are the property of their respective companies.
Changes or modifications to this unit not expressly approved by the party responsible for compliance could void the user’s authority to operate the equipment.
Document Number: AW-09293-001 Rev. 005
Imaging System
The ThinPrep
®
®
The ThinPrep
Imaging System
Operation Summary and Clinical Information
The ThinPrep® Imaging System
A. INTENDED USE
The Hologic ThinPrep® Imaging System (Imager) is a device that uses computer imaging
technology to assist in primary cervical cancer screening of ThinPrep Pap Test slides for the
presence of atypical cells, cervical neoplasia, including its precur sor lesio ns (Low Grade Sq uamou s
Intraepithelial Lesions, High Grade Squamous Intraepithelial Lesions), and carcinoma as well as all
other cytologic criteria as defi ned by 2001 B et hesda Sy stem : Term inol ogy for Rep orti ng Re sults of
Cervical Cytology
1
.
B. SUMMARY AND EXPLANATION OF THE SYSTEM
The ThinPrep Imaging System is an automated imaging and review system for use with ThinPrep
Pap Test slides. It combines imaging technology to identify microscopic fields of diagnostic interest
with automated stage movement of a microscope in order to locate these fields. In routine use, the
ThinPrep Imaging System selects 22 fields of view for a Cytotechnologist to review. Following
review of these fields, the Cytotechnologist will either complete the diagnosis if no abnormalities
are identified or review the entire slide if any abnormalities are identified. The ThinPrep Imaging
System also allows the physical marking of locations of interest for the Cytopathologist.
C. PRINCIPLES OF OPERATION
The ThinPrep Imaging System consists of an Image Processor and one, or more, Review Scopes.
The system makes use of computer imaging to select fields of view for presentation to a
Cytotechnologist on a Review Scope. Slides used with this system must first be prepared on a
ThinPrep 2000 or 3000 Processor, and stained with ThinPr ep Stain.
The Imaging Processor acquires and processes image data from the slides to identify diagnostically
relevant cells or cell groups based on an imaging algorithm that considers cellular features and
nuclear darkness. During slide imaging, the alphanumeric slide accession identifier is recorded and
the x and y coordinates of 22 fields of interest are stored in the computer database. This computer
also coordinates the communication of information between the Image Processor and the Review
Scopes.
After image processing, slides are distributed to Cytotechnologists for review utilizing the Review
Scopes. The Review Scope is a microscope with an automated stage to facilitate the locating of the
22 fields containing the cells of interest. Additionally, the Review Scope provides a method for
automated marking of objects for further review. Slides are individually loaded onto the Review
Scope stage, the alphanumeric slide accession identifier is automatically scanned and the stored x
and y coordinates representing fields of interest for that slide are electronically downloaded from
the computer to the Review Scope. The Cytotechnologist then uses a keypad to step through each
of the fields of interest (Autolocate). If the Cytotechnologist identifies any of these fields as
containing abnormal objects, that field may be marked electronically. The Review Scope will guide
the Cytotechnologist to conduct a review of the entire cell spot for any slide that h as had fields
electronically marked (Autoscan). The Cytotechnologist determines specimen adequacy and the
presence of infections during the review of the 22 fields of view presented by the ThinPrep Imaging
System. Either of two method s can be used to determine specimen adequacy. The first method is to
count cells and determine the average number of cells in the 22 fields of view presented by the
Imager. The second method is to count and determine the average number of cells in 10 fields of
view across the diameter of the cell spot. Either method will enable the Cytotechnologist to
determine if the minimum cells, as recommended by Bethesda System 2001 criteria, are present on
the slide. At the conclusion of the slide review electronically marked objects are automatically ink
marked. Any x and y coordinates representing marked locations al ong with a slide com pletion status
are then electronically transmitted back to the computer for storage.
MAN-03938-001 Rev. 002 page 2 of 23
D. LIMITATIONS
Only pers onnel who ha ve bee n approp riately traine d should operat e the ThinPrep® Imaging System
Image Processor or Review Scope.
All slides that undergo primary automated screening with the Image Processor require manual
rescreening of the selected fields of view by a Cytotechnologist using a Review Scope.
The ThinPrep Imaging System is only indicated for use with the ThinPrep Pap Test.
The laboratory Technical Supervisor should establish individual workload limits for personnel using the
ThinPrep Imaging System. The maximum daily limit specified is only an upper limit and should never be used
as an expectation for daily productivity or as a performance target.
The ThinPre p Im aging Sy ste m has n ot bee n pro ven t o be safe or effective at workload levels which
exceed product labeling.
ThinPrep slides with fiducial marks must be used.
Slides must be stained using the ThinPrep Stain according to the applicable ThinPrep Imaging
System slide staining protocol.
Slides should be clean and free of debris before being placed on the system.
The slide coverslip should be dry and located correctly.
Slides that are broken or poorly coverslipped should not be used.
Slides used with the ThinPrep Imaging System must contain properly formatted accession number
identification information as described in the operator’s manual.
Slides once successfully imag ed on the Image Processor cannot be imaged again.
The performance of the ThinPrep Imaging System using slides prepared from reprocessed sample
vials has not been evaluated; therefore it is recommended that these slides be manually reviewed.
E. WARNINGS
The Imager generates, uses, and can radiate radio frequency energy and may cause interference to
radio communications.
A Hologic authorized service representative must install the ThinPrep Imaging System.
F. PRECAUTIONS
Caution should be used when loading and unloading glass slides on the ThinPrep Imaging System
to prevent slide breakage and/or injury.
Care should be taken to assure that slides are correctly oriented in the ThinPrep Imaging System
cassettes to prevent rejection by the system.
Partially processed slide cassettes should not be removed from the Image Processor, as data m ay be
lost.
The Image Processor should be place d on a flat, sturdy surface away from any vibrating machinery
to assure proper operation.
MAN-03938-001 Rev. 002 page 3 of 23
G. PERFORMANCE CHARACTERISTICS
A multi-center, two-armed clinical study was performed over an eleven (11) month period at four
(4) cytology laboratory sites within the United States. The objective of the study entitled “MultiCenter Trial Evaluating the Primary Screening Capability of the ThinPrep
to show that routine screening of ThinPrep Pap Test slides using the ThinPrep Imaging System is
equivalent to a manual review of ThinPrep slides for all categories used for cytologic diagnosis
(specimen adequacy and descriptiv e diagnosis) as defined by the Bethesda System criteria
The two-arm study approach allowed a comparison of the cytologic interpretation (descriptive
diagnosis and specimen adequacy) from a single ThinPrep prepared slide, screened first using
standard laboratory cervical cytology practices (Manual Review) and then after a 48 day time lag
were screened with the assistance of the ThinPrep Imaging System (Imager Review). A subset of
slides from the study were reviewed and adjudicated by a panel of three (3) independent
Cytopathologists to determine a consensus diagnosis. The consensus diagnosis was used as a “gold
standard” for truth to evaluate the results of the study.
G.1 LABORATORY AND PATIENT CHARACTERISTICS
Of the 10,359 subjects in the study, 9,550 met the requirements for inclusion in the descriptive
diagnosis analysis. During the study, 7.1% (732/10,359) slides could not be read on the Imager and
required a manual review during the Imager Review arm. Excessive number of air bubbles on the
slides was the leading contributor. Additional factors included focus pr oblems, slide density, slide
identification read failures, slides detected out of position, multip le slides seated within a cassette
slot and slides that had already been imaged. The cytology laboratories participating in the study
were comprised of four centers. All sites selected had extensive experience in the processing and
evaluation of gynecologic ThinPrep slides, and were trained in the use of the ThinPrep Imaging
System. The study population represented diverse geographic region s and subject populations of
women who would undergo cervical screening with the ThinPrep Imaging System in normal clinical
use. These sites included both women being routinely screened (screening population) and patients
with a recent previous cervical abnormality (referral population) . The characteristics of the study
sites are summarized in Table 1.
Table 1: Site Characteristics
®
Imaging System” was
2
.
Site 1 2 3 4
Low Risk Population
High Risk Population
HSIL+ prevalence
ThinPrep Pap Tests Per Year
Number of Cytotechnologists
Number of Cytotechnologists in Study
Number of Cytopathologists
Number of Cytopathologists in Study
88% 82% 90% 94%
12% 18% 10% 6%
1.1% 0.7% 0.4% 0.6%
120,000 70,200 280,000 105,000
14 9 32 11
2 2 2 2
6 5 6 14
1 2 1 2
MAN-03938-001 Rev. 002 page 4 of 23
G.2 DESCRIPTIVE DIAGNOSIS SENSITIVITY AND SPECIFICITY ESTIMATES
A panel of three independent Cytopathologists adjudicated slides from all discordant (one-grade or
higher cytologic difference) descriptive diagnosis cases (639), all concordant positive cases (355)
and a random 5% subset of the 8550 negative concordant cases (428). The Cytopathologists on the
adjudication panel were board-certified, all of whom had a subspecialty certification in
Cytopathology. Their experience levels in Cytopathology ranged from 6 to 12 years. Two of the
adjudicators were from university practices and one adjudicator was from a private medical center.
The volumes for the adjudicator’s institutions ranged from 12,0 00 to 30,000 ThinPrep
annually.
A consensus diagnosis was defi ned as agreement by at least 2 of 3 Cytopathologists. All sli des sent
to the panel of Cytopathologists were not identified by site nor ordered in any fashion. When a
consensus diagnosis could not be obtained by at least 2 of 3 Cytopathologists, the full panel of
Cytopathologists reviewed each case simul taneously usin g a mult i-headed mi croscope to determ ine
a consensus diagnosis.
The adjudicated results were used as a “gold standard” to define the following major “true”
descriptive diagnosis classifications of the Bethesda System: Negative, ASCUS, AGUS, LSIL,
HSIL, Squamous Cell Carcinoma (SQ CA) and Glandular Cell Carcinoma (GL CA). Estimates of
sensitivity and specificity together with 95% confidence intervals were calculated for the Manual
Review and Imager Review arms of the study. The differences in sensitivity and specificity between
the two arms, together with their 95% confidence intervals were also calcu lated. Among the random
5% subset of 8,550 cases (428 slides) that were found to be negative by both arms and adjudicated,
there were 425 “true” negative and 3 “true” ASCUS slides. A multiple imputation technique was
used to adjust the numbers of true positives and true negatives for the 8,550 negative concord ant
cases based on the 5% of cases that were adjudicated
3
.
®
Pap Tests
Tables 2-4 below summarize the descriptive diagnosis sensitivity and specificity estimates with 95%
confidence intervals for each of the four sites and all sites combined for “true” ASCUS+, LSIL+
and HSIL+.
Table 2: Adjudicated Review Versus Imager And Manual Reviews ASCUS+
Descriptive Diagnosis Summary.
Sensitivity is a percent of “true” ASCUS+ (combined ASCUS, AGUS, LSIL, HSIL, SQ CA and GL CA) slides
classified in either study arm as ASCUS+ and specificity is a percent of “true” Negative slides classified in either
study arm as Negative.
Sensitivity Specificity
Site/
Number
Cases
Site 1
180
Site 2
230
Site 3
103
Site 4
179
All
692
Numbers in parentheses represent 95% confidence intervals.
Manual Imager Difference
77.2%
(70.4, 83.1)
63.1%
(56.5, 69.3)
80.6%
(71.6, 87.7)
87.2%
(81.4, 91.7)
75.6%
(72.2, 78.8)
78.3%
(71.6, 84.1)
77.5%
(71.4, 82.6)
94.2%
(87.8, 97.8)
84.4%
(78.2, 89.4)
82.0%
(78.8, 84.8)
+1.1%
(-5.8, 8.0)
+14.4%
(8.2, 20.5)
+13.6%
(4.3, 22.9)
-2.8%
(-10.6, 5.0)
+6.4%
(2.6, 10.0)
Site/
Number
Cases
Site 1
2132
Site 2
2210
Site 3
2196
Site 4
2313
All
8851
Manual Imager Difference
98.7%
(98.1, 99.1)
95.8%
(94.9, 96.6)
98.5%
(97.9, 99.0)
97.3%
(96.6, 97.9)
97.6%
(97.2, 97.9)
99.2%
(98.7, 99.5)
96.1%
(95.2, 96.9)
98.8%
(98.3, 99.2)
97.0%
(96.2, 97.7)
97.8%
(97.4, 98.1)
+0.4%
(-0.1, 1.0)
+0.3%
(-0.7, 1.3)
+0.4%
(-0.3, 1.0)
-0.3%
(-1.1, 0.5)
+0.2%
(-0.2, 0.6)
The results presented in Table 2 show that for ASCUS+, the increase in sensitivity of the Imager
Review over the Manual Review was statistically significant with the lower limit of the 95%
confidence interval being 2.6% for all sites combined. The observed difference between sensitivities
for ASCUS+ varied among the sites from –2.8% with a 95% confi dence int erval of (–10.6%; 5.0%)
to +14.4% with a 95% confidence interval of (8.2%; 20.5%) . The difference in specificity results
between the Imager Review and the Manual Review was not statistically significant with a 95%
confidence interval of -0.2% to +0.6%. The observed differences between specificities varied am ong
the sites from –0.3% to +0.4%.
MAN-03938-001 Rev. 002 page 5 of 23
Table 3: Adjudicated Review Versus Imager Review LSIL+ Descriptive Diagnosis
Summary for Each Site and All Sites Combined.
Sensitivity is a percent of “true” LSIL+ (combined LSIL, HSIL, SQ CA and GL CA) slides classified in either study
arm as LSIL+ and specificity is a percent of “true” Non-LSIL+ (combined Negative, ASCUS, AGUS) slides classified
in either study arm as Non-LSIL+.
Sensitivity Specificity
Site/
Number
Cases
Site 1
104
Site 2
98
Site 3
62
Site 4
111
All
375
Numbers in parentheses represent 95% confidence intervals.
Manual Imager Difference
84.6%
(76.2, 90.9)
70.4%
(60.3, 79.2)
77.4%
(65.0, 87.1)
84.7%
(98.1, 99.1)
79.7%
(75.3, 83.7)
82.7%
(74.0, 89.4)
72.4%
(62.5, 81.0)
85.5%
(74.2, 93.1)
78.4%
(76.6, 90.8)
79.2%
(74.7, 83.2)
-1.9%
(-9.5, 5.6)
+2.0%
(-6.9, 11.0)
+8.1%
(-4.0, 20.1)
-6.3%
(-14.7, 2.1)
-0.5%
(-5.0, 4.0)
Site/
Number
Cases
Site 1
2208
Site 2
2342
Site 3
2237
Site 4
2381
All
9168
Manual Imager Difference
98.7%
(98.1, 99.1)
99.3%
(98.8, 99.6)
99.2%
(98.7, 99.5)
98.7%
(98.2, .99.2)
99.0%
(98.8, 99.2)
99.3%
(98.9, 99.6)
98.9%
(98.4, 99.3)
99.5%
(99.1, 99.8)
98.7%
(98.1, 99.1)
99.1%
(98.9, 99.3)
+0.6%
(0.1, 1.0)
-0.4%
(-0.8, .001)
+0.3%
(-0.1, 0.6)
-0.08%
(-0.6, 0.4)
+0.09%
(-0.1, 0.3)
The results presented in Table 3 show that the difference between sensitivities of the Imager Review
and Manual Review arms for LSIL+ for all sites co mbined was not statistically significant with a
95% confidence interval of –5.0% to +4.0%. The observed difference between sensitivities for
LSIL+ varied among the sites from –6.3% with a 95% confidence interval of (–14.7%; 2.1%) to
+8.1% with a 95% confidence interval of (–4.0%; 20.1%). The difference in specificity results
between the Imager Review and the Manual Review was not statistically significant with a 95%
confidence interval of -0.1% to +0.3%. The observed differences between specificities varied am ong
the sites from –0.4% to +0.6%.
Table 4: Adjudicated Review Versus Imager Review HSIL+ Descriptive Diagnosis
Summary for Each Site and All Sites Combined.
Sensitivity is a percent of “true” HSIL+ (combined HSIL, SQ CA and GL CA) slides classified in either study arm as
HSIL+ and specificity is a percent of “true” Non-HSIL+ (combined Negative, ASCUS, AGUS, LSIL) slides classified
in either study arm as Non-HSIL+.
Sensitivity Specificity
Site/
Number
Cases
Site 1
38
Site 2
40
Site 3
22
Site 4
39
All
139
Numbers in parentheses represent 95% confidence intervals.
Manual Imager Difference
89.5%
(75.2, 97.1)
72.5%
(56.1, 85.4)
72.7%
(49.8, 89.3)
61.5%
(44.6, 76.6)
74.1%
(66.0, 81.2)
92.1%
(78.6, 98.3)
70.0%
(53.4, 83.4)
86.4%
(65.1, 97.1)
74.4%
(57.9, 87.0)
79.9%
(72.2, 86.2)
2.6%
(-8.9, 14.1)
-2.5%
(-15.4, 10.4)
+13.6%
(-0.7, 28.0)
+12.8%
(-1.7, 27.4)
+5.8%
(-1.1, 12.6)
Site/
Number
Cases
Site 1
2274
Site 2
2400
Site 3
2277
Site 4
2453
All
9404
Manual Imager Difference
98.8%
(98.3, 99.2)
99.8%
(99.5, 99.9)
99.7%
(99.4, 99.9)
99.5%
(99.2, 99.8)
99.4 %
(99.2, 99.6)
99.5%
(99.1, 99.8)
99.6%
(99.2, 99.8)
99.7%
(99.4, 99.9)
99.8%
(99.5, 99.9)
99.6%
(99.5, 99.7)
+0.7%
(0.2, 1.2)
-0.1%
(-0.3, .09)
0%
(-0.2, 0.2)
+0.3%
(-0.003, 0.6)
+0.2%
(0.06, 0.4)
MAN-03938-001 Rev. 002 page 6 of 23
The results presented in Table 4 show that the difference between sensitivities of the Imager Review
and Manual Review arms for HSIL+ for all sites combined was not statistically significan t with a
95% confidence interval of -1.1% to +12.6%. The observed difference between sensitivities for
HSIL+ varied among the sites from –2.5% with a 95% confidence interval of (–15.4%; 10.4%) to
+13.6% with a 95% confidence interval of (–0.7%; 28.0%). The increase in specificity of the Imager
Review over the Manual Review was statistically significant with a 95% confidence interval of
+0.06% to +0.4%. The observed differences between specificities varied among the sites from –
0.1% to +0.7%.
Tables 5-9 show the performance of the Imager Review and Manual Review compared to the final
consensus diagnosis made by the adjudication panel (truth) for the following major descriptive
diagnosis classifications of the Bethesda System: Negative, ASCUS, AGUS, LSIL, HSIL, Cancer*
(CA)
*Includes SQ CA and GL CA.
Abbreviations for Diagnoses: NEG = Normal or negative, ASCUS = Atypical Squamous Cells of Undetermined Significance,
AGUS = Atypical Glandular Cells of Undetermined Significance, LSIL = Low-grade Squamous Intraepithelial Lesion, HSIL
= High-grade Squamous Intraepithelial Lesion, SQ CA = Squamous Cell Carcinoma, GL CA = Glandular Cell
Adenocarcinoma.
All 786 Cases Determined To Be Negative By Adjudication
Table 5: 6x6 “True Negative” Contingency Table For All Sites Combined
Unadjudicated Manual Review Arm Diagnosis
NEG ASCUS AGUS LSIL HSIL CA TOTAL
NEG 425 138 6 10 6 2 587
ASCUS 130 39 1 3 - - 173
AGUS 5 - - - - - 5
LSIL 9 5 - 2 - - 16
HSIL 1 1 - - 3 - 5
CA - - - - - - 0
Unadjudicated Imager
Review Arm Diagnosis
TOTAL 570 183 7 15 9 2 786
Among the 786 cases determined by the adjudication panel to be Negative, 587 (74.7%) cases in the
Imager Review arm and 570 (72.5%) cases in the Manual Review arm were diagnosed as Negative
and 21 (2.7%) cases in the Imager Review arm and 26 (3.3%) cases in the Manual Review arm were
diagnosed as LSIL+.
Table 6: 6x6 “True ASCUS” Contingency Table For All Sites Combined
All 251 Cases Determined To Be ASCUS By Adjudication
Unadjudicated Manual Review Arm Diagnosis
NEG ASCUS AGUS LSIL HSIL CA TOTAL
NEG 3 32 - 7 3 - 45
ASCUS 70 47 1 20 4 - 142
AGUS 1 - - - - - 1
LSIL 6 21 - 16 7 - 50
HSIL 2 3 - 5 1 1 12
CA 1 - - - - - 1
Unadjudicated Imager
Review Arm Diagnosis
TOTAL 83 103 1 48 15 1 251
Among the 251 cases determi ned by the adjudication panel to be ASCUS, 142 (56.6%) cases in the
Imager Review arm and 103 (41.0%) cases in the Manual Review arm were diagnosed as ASCUS
and 45 (17.9%) cases in the Imager Review arm and 83 (33.1%) cases in the Manual Review arm
were diagnosed as Negative.
MAN-03938-001 Rev. 002 page 7 of 23
Table 7: 6x6 “True AGUS” Contingency Table For All Sites Combined
All 10 Cases Determined To Be AGUS By Adjudication
Unadjudicated Manual Review Arm Diagnosis
NEG ASCUS AGUS LSIL HSIL CA TOTAL
NEG - 2 1 - 1 - 4
ASCUS - - 1 - - - 1
AGUS 2 - 1 - - 1 4
LSIL - - - - - - 0
HSIL - - - - - - 0
CA - - - - - 1 1
Unadjudicated Imager
Review Arm Diagnosis
TOTAL 2 2 3 0 1 2 10
Among the 10 cases determined by the adjudication panel to be AGUS, 4 (40.0%) cases in the
Imager Review arm and 3 (30.0%) cases in the Manual Review arm were diagnosed as AGUS and
4 (40.0%) cases in the Imager Review arm and 2 (20.0%) cases in the Manual Review arm were
diagnosed as Negative.
Table 8: 6x6 “True LSIL” Contingency Table For All Sites Combined
All 236 Cases Determined To Be LSIL By Adjudication
Unadjudicated Manual Review Arm Diagnosis
NEG ASCUS AGUS LSIL HSIL CA TOTAL
NEG - 4 - 12 1 - 17
ASCUS 13 16 - 20 1 - 50
AGUS - - - - - - 0
LSIL 8 20 - 115 12 - 155
HSIL - - - 5 9 - 14
CA - - - - - - 0
Unadjudicated Imager
Review Arm Diagnosis
TOTAL 21 40 0 152 23 0 236
Among the 236 cases determined by the adjudication panel to be LSIL, 155 (65.6%) cases in the
Imager Review arm and 152 (64.4%) cases in the Manual Review arm were diagnosed as LSIL and
17 (7.2%) cases in the Imager Review arm and 21 (8.9%) cases in the Manual Review arm were
diagnosed as Negative.
Table 9: 6x6 “True HSIL” Contingency Table For All Sites Combined
All 138 Cases Determined To Be HSIL By Adjudication
Unadjudicated Manual Review Arm Diagnosis
NEG ASCUS AGUS LSIL HSIL CA TOTAL
NEG - 1 - - 1 - 2
ASCUS 2 4 - 2 1 - 9
AGUS - - - - - - 0
LSIL 1 - - 10 6 - 17
HSIL 3 3 1 9 91 1 108
CA - - - - 1 1 2
Unadjudicated Imager
Review Arm Diagnosis
TOTAL 6 8 1 21 100 2 138
MAN-03938-001 Rev. 002 page 8 of 23
Among the 138 cases determined by the adjudication panel to be HSIL, 108 (78.3%) cases in the
Imager Review arm and 100 (72.5%) cases in the Manual Review arm were diagnosed as HSIL and
2 (1.4%) cases in the Imager Review arm and 6 (4.3%) cases in the Manual Review arm were
diagnosed as Negative.
There was one (1) squamous cell carcinoma (SQ CA) case resulting from adjudication. It was
diagnosed as HSIL in the Imager Review arm and SQ CA in the Manual Review arm.
Table 10 shows the study subjects unadjudicated descriptive diagnosis marginal frequencies for
benign cellular changes for all sites combined.
Table 10: Unadjudicated Marginal Frequencies Summary of Descriptive Diagnosis
for Benign Cellular Changes – All Sites Combined.
Manual Review Imager Review
Number of Patients: 9550 9550
Descriptive Diagnosis N % N %
Benign Cellular Changes:
Infection:
Trichomonas Vaginalis 8 0.1 8 0.1
Fungal organisms consistent with Candida spp. 47 0.5 31 0.3
Predominance of coccobacilli 71 0.7 60 0.6
Bacteria consistent with Actinomyces spp. 1 0.0 1 0.0
Cellular Changes associated with Herpes virus 1 0.0 1 0.0
Other Infection 1 0.0 0 0.0
Reactive Cellular Changes Associated with:
Inflammation 218 2.3 156 1.6
Atrophic with inflammation (atrophic vaginitis) 68 0.7 46 0.5
Radiation 0 0.0 0 0.0
Intrauterine contraceptive device (IUD) 0 0.0 0 0.0
Other Reactive Cellular Change 34 0.4 14 0.1
Note: Some patients had more than one diagnostic subcategory.
405 4.2 293 3.1
The Manual Review showed a higher rate of Benign Cellular Changes (405) than the Imager
Review cases (293).
G.3 ANALYTICAL PERFORMANCE OF THINPREP IMAGING SYSTEM FOR
DETECTION OF CERVICAL CANCER USING THINPREP
®
PAP TEST SLIDES
FRESHLY PREPARED FROM ARCHIVAL SAMPLES
This analytical study was conducted to compare the Bethesda System 2001 results, obtained by a
Cytotechnologist and a Cytopathologist, when their review was limited to 22 fields that were selected
by the ThinPrep Imaging System, to their diagnostic results obtained from their independent blinded
review of the entire cell spot on the ThinPrep Pap Test slides. All of the reviews were performed in an
independent and blinded manner. The test materials consisted of 33 archival PreservCyt-preserved
cervical samples that had been previously diagnose d a s AG US o r cancer . One ThinPrep Pap Test slide
was freshly prepared from each of the 33 original PreservCyt vials. All of the ThinPrep slides used in
the study were made on the TP-2000 processor and stained with ThinPrep Stain. Based on the cur rent
cervical cancer prevalence rate in the United States, 33 cases of cervical cancer would represent the
number of invasive cervical cancer cases in a population of approximately 275,000 women
4
.
Initially, a board-certified Cytopathologist manually reviewed all of the fields on the ThinPrep Pap Test
slides and identified and recorded the number of individual cancer cells and clusters of cancer cells that
were present. For this part of the study, the Cytopathologist was not required to record any other cells
with other Bethesda System 2001 diagnoses. The 33 cases included slides that represented both rare
numbers of cancer cells (5-20 per slide), and numerous cancer cells (>20/slide). Cancer cells were
categorized according to Bethesda System 2001 criteria for Glandular Cancer, Ade nocarcinom a-in-situ
and Squamous Cell Cancer. Each slide was then processed on a ThinPrep Imaging System. The
Cytotechnologist then reviewed only the 22 fields of view presented by the Autolocate mode of the
Review Scope. No review outside of the selected 22 fields of view was permitted. For each field of
view, the Cytotechnologist counted and recorded all abnormal cell types based on the following seven
Bethesda System classifications: ASCUS, LSIL, HSIL, AGUS, Glandular Cancer, Squamous Cell
Carcinoma and Adenocarcinoma-In-Situ.
MAN-03938-001 Rev. 002 page 9 of 23
Finally, the same Cytopathologist who had conducted the manual review of the entire ThinPrep
®
Pap
Test slide, independently re-reviewed the slides using the identical method used by the
Cytotechnologists. The Cytopathologist was blinded from the original manual review results. For each
of the 22 fields of view selected by the ThinPrep Imaging System, the Cytopathologist verified and
recorded the number of individual cancer cells, clusters of cancer cells, and any other abnormalities
present. Table 11 summarizes the results from this study:
Table 11: Summary of Results From Restricted Analytical Cancer Study
Cytopathologist Full Manual
Review
10 Glandular Cancer
1 Adenocarcinoma In-situ 1 Adenocarcinoma In-Situ 1 Adenocarcinoma In-Situ
22 Squamous Cell Carcinoma
Total = 33 Total = 33 Total = 33
Cytotechnologist Review of Imager
Identified 22 Fields of View *
5 Glandular Carcinoma
1 Squamous Cell Carcinoma
1 Adenocarcinoma In-situ
2 HSIL/AGUS
1 ASC-H/ASC-US
3 Glandular Carcinoma
12 Squamous Cell Carcinoma
1 Squamous/Glandular Carcinoma
2 Adenocarcinoma In-situ
4 HSIL
Cytopathologist Review of
Imager Identified 22 Fields
of View **
7 Glandular Carcinoma
1 Squamous Cell Carcinoma
1 AGUS
1 HSIL
21 Squamous Cell Carcinoma
1 Adenocarcinoma In-situ
* In the intended use of the ThinPrep Imaging System (Imager), the Cytotechnologist would perform a full manual slide review
of each of these cases and pass them on to a Cytopathologist for further review.
* *In the intended use of the ThinPrep Imaging System (Imager), the Cytopathologist would perform a full manual slide review of
each of these cases.
The results in Table 11 demonstrate the ability of the ThinPrep Imaging System to successfully identify
abnormalities in the 22 fields of view presented during the Autolocate mode of slide review. In all 33
cases in this study, the ThinPrep Imaging System identified and presented cells among the 22 fields of
view that were categorized as Cancer, HSIL, AGUS or ASCUS. In addition, the Cytopathologists’
confirming review of the identical 22 fields of view showed consistent, but slightly improved results
with all cases being categorized as Cancer, HSIL or AGUS. Consistent with the intended use of the
ThinPrep Imaging System, the Cytotechnologists’ diagnoses in every one of these 33 cas es would have
invoked the full slide Autoscan mode that would require a Cytotechnologist to screen the entire slide
before making a final diagnosis. The results of this study indicate that ThinPrep Imaging System will
accurately lead to a full manual slide review for the detection of cervical cancer or its precursor lesi ons.
G.4 SPECIMEN ADEQUACY STUDY
Of the 10,359 subjects in the study, 9627 met the requirements for inclusion in the specimen adequ acy
analysis.
MAN-03938-001 Rev. 002 page 10 of 23
Table 12: Unadjudicated Marginal Frequencies Summary of Specimen Adequacy
Results – All Sites Combined.
Manual Review Imager Review
Number of Patients:
Descriptive Diagnosis N % N %
Satisfactory for Evaluation
Satisfactory but Limited by
Endocervical Component Absent 1196 12.4 1397 14.5
Scant Squamous Epithelial Component 92 1.0 102 1.1
Obscuring Blood 45 0.5 17 0.2
Obscuring Inflammation 69 0.7 68 0.7
No Clinical History 982 10.2 933 9.7
Cytolysis 4 0.0 2 0.0
Other 6 0.1 33 0.3
Unsatisfactory for Evaluation
Endocervical Component Absent 6 0.1 0 0.0
Scant Squamous Epithelial Component 35 0.4 22 0.2
Obscuring Blood 17 0.2 2 0.0
Obscuring Inflammation 8 0.1 5 0.1
No Clinical History 2 0.0 2 0.0
Cytolysis 0 0.0 0 0.0
Other 2 0.0 0 0.0
Note: Some patients had more than one diagnostic subcategory.
9627 9627
7375 76.6 7346 76.3
2186 22.7 2252 23.4
66 0.7 29 0.3
For SAT cases, there was agreement between the Manual Review cases (7375) and the Imager
Review cases (7346). For SBLB cases, there is agreement between the Manual Review cases (2186)
and the Imager Review cases (2252). Unsatisfactory cases were greater in the Manual Review cases
(66) versus the Imager Review cases (29).
The adjudicated results were used as a “gold standard” to define “true” specimen adequacy
classifications of the Bethesda System: SAT/SBLB and UNSAT. There were 58 “true” UNSAT
cases and 9569 “true” SAT/SBLB cases.
Table 13 below summarizes specimen adequacy performance for the Imager Review and Manual
Review arms for all four sites and all sites combined using the Bethesda System 1991 criteria.
Table 13: Adjudicated Review Versus Imager Review Specimen Adequacy
Summary for All Sites and All Sites Combined.
Sensitivity is a percent of “true” UNSAT slides classified in either study arm as UNSAT and specificity is a percent of
“true” SAT/SBLB slides classified in either study arm as SAT/SBLB.
Sensitivity Specificity
Site/
Number
Cases
Site 1
21
Site 2
6
Site 3
5
Site 4
26
All
58
CI*
*95% Confidence Interval
Manual Imager Difference
0%
(0/21)
100%
(6/6)
80.0%
(4/5)
30.8%
(8/26)
29.3%
(17/58)
(18.1, 42.7)
0%
(0/21)
16.7%
(1/6)
60.0%
(3/5)
19.2%
(5/26)
13.8%
(8/58)
(6.1, 25.4)
0.0%
(0/21)
-83.3%
(-5/6)
-20.0%
(-1/5)
-11.5%
(-3/26)
-15.5%
(-9/58)
(-25.9, -5.0)
All ThinPrep
®
slides that produced discordant unsatisfactory determinations (Manual Review arm
Site/
Number
Cases
Site 1
2292
Site 2
2476
Site 3
2323
Site 4
2478
All
9569
CI*
Manual Imager Difference
100%
(2292/2292)
98.9%
(2449/2476)
99.2%
(2304/2323)
99.9%
(2475/2478)
99.5%
(9520/9569)
(99.3, 99.6)
100%
(2292/2292)
99.6%
(2465/2476)
99.7%
(2315/2323)
99.9%
(2476/2478)
99.8%
(9548/9569)
(99.7, 99.9)
0.0%
(0/2292)
+0.6%
(16/2476)
+0.5%
(11/2323)
+0.04%
(1/2478)
+0.3%
(28/9569)
(0.2, 0.4)
MAN-03938-001 Rev. 002 page 11 of 23
vs. Imager Review arm) during the clinical study were assessed in an additional clinical support
study to compare the method used for specimen adequacy in the clinical study with a control cell
count of the slides and 3 differ ent methods as foll ows: (1) Manual assessment of specim en adequacy
on the entire microscope slide based on ThinPrep Bethesda System 1991 criteria; (2) Using the
“diameter” method of Bethesda Syst em 2001, which requi res that t he Cyt otechn ologi st c ounts cel ls
in 10 fields of view along the diameter of the cell spot and calculate the number of cells on the slide;
(3) Having the Cytotechnologist count the cells in the 22 fields o f view pre sented by t he system and
calculate the number of cells on the slide.
This additional support study demonstrated that the Bethesda System 1991 estimation methods,
including the method used in the clinical study, do not generate similar specimen adequacy
determinations when compared against each other or with the control method. Therefore, the
recommended methods for determining specimen adequacy on the ThinPrep Imaging System are
(1) the Bethesda System 2001 count of fields along a diagonal of the cell spot or (2) counting the
cells in the 22 fields-of-view selected by the ThinPrep Imager System. Refer to the ThinPrep
Imaging System Review Scope Operator’s Manual for instructions on the proper use of these
methods.
G.5 CYTOTECHNOLOGIST SCREENING RATES
Daily Cytotechnologist screening rates were recorded throughout the duration of the clinical study.
The study was conducted in a manner designed to reproduce actual clinical conditions. Eight (8)
Cytotechnologists participated in the study; two (2) at each clinical site. The experience levels of
the Cytotechnologists ranged from 5 to 23 y ears. During the study the Cytotechnologist’s screening
times for the Imager Review arm included automated screening of the 22 fields of view with
subsequent full side review of abnormal slides. A full slide review co nsists of approximately 120
fields of view. The number of hours each Cytotechnologist screened slides per day varied due to
logistical issues and scheduling. With the ThinPrep Imaging System, Cytotechnologist screening
rates were uniformly faster than the Manual Review method.
Table 14 summarizes the Cytotechnologist screening rates for both the Imager Review and the
Manual Review methods. The total number of slides reviewed in the study and the average number
of hours screened per day are presented for each Cytotechnologist and site. Screening rates
(extrapolated to an 8 hour wo rkday) are pres ented as the low, average and high daily screening rates
achieved by each Cytotechnologist and site. The low and high daily rates were selected from the
lowest and highest daily hourly rates, respectively, and are extrapolated to 8 hours.
MAN-03938-001 Rev. 002 page 12 of 23
Table 14: Cytotechnologist Screening Rates
Site/CT
Review
Methods
Site 1 Manual 2568 7.4 49 69 94
1-1 Manual 1284 7.5 49 60 72
1-2 Manual 1284 7.3 70 78 94
Site 2 Manual 2686 7.7 40 68 80
2-1 Manual 1348 7.6 40 71 80
2-2 Manual 1338 7.8 55 66 75
Site 3 Manual 2738 7.9 20 80 101
3-1 Manual 1368 7.9 63 82 91
3-2 Manual 1370 7.8 20 78 101
Site 4 Manual 2612 7.6 42 69 94
4-1 Manual 1305 8.2 59 75 84
4-2 Manual 1307 6.9 42 63 94
Table 15 summarizes the Manual Review versus the Imager Review for ASCUS+ and HSIL+
sensitivity and specificity by site. The table also presents the prevalence of ASCUS+, LSIL+, and
HSIL+ among the reviewed slides and the respective screening daily rates of each review method.
The daily screening rates are extrapolated to an 8-hour workday and are presented as the low,
average and high daily screening rates by site.
Table 15: Screening Rates, Prevalence of ASCUS+, LSIL+, HSIL+, and Respective
Performance for ASCUS+ and HSIL+.
Site % of
ASCUS+
Site 1 7.7% 4.5% 1.6%
Site2 9.2% 4.0% 1.6%
Site 3
Site 4 7.2% 4.5% 1.6%
4.4% 2.7% 1.0%
% of
LSIL+
% of
HSIL+
Total
Number of
Slides
Evaluated
Average
Number of
Hours
Screened Per
Extrapolated Daily Rates
(8-hour workday)
Low
Day
Average
Day
High
Day
Day
Imager 2297 6.0 107 153 206
Imager 1168 6.1 117 153 182
Imager 1129 5.9 107 154 206
Imager 2665 7.8 69 109 131
Imager 1309 7.9 97 110 118
Imager 1356 7.7 69 109 131
Imager 2726 4.5 148 204 320
Imager 1460 4.2 167 230 320
Imager 1266 4.7 148 178 212
Imager 2524 5.1 86 138 198
Imager 1252 5.1 86 150 190
Imager 1272 5.0 109 126 198
Review
Methods
Manual 49 69 94 77.2%
Imager 107 153 206 78.3% 99.2% 92.1% 99.5%
Manual 40 68 80 63.1%
Imager 69 109 131 77.7% 96.1% 70.0% 99.6%
Manual 20 80 101 80.6%
Imager 148 204 320 94.2% 98.8% 78.6% 99.7%
Manual 42 69 94 87.2%
Imager 86 138 198 84.4% 97.0% 74.4% 99.8%
Extrapolated Daily Rates
(8-hour workday)
Low
Day
Average
Day
High
Day
Performance for
ASCUS+
Sensitivity Specificity Sensitivity Specificity
98.7%
+1.1%
+14.4%
+13.6%
-2.8%
95.8%
98.5%
97.3%
+0.4%
+0.3%
+0.4%
-0.3%
89.5%
72.5%
64.3%
61.5%
Performance for
HSIL+
98.8%
+2.6%
99.8%
-2.5%
99.7%
+13.6%
99.5%
+12.8%
+0.7%
-0.1%
0%
+0.3%
The clinical study data show that the screening rates achieved with the ThinPrep® Imaging System
resulted in sensitivity or specificity values that fall within acceptable limits.
MAN-03938-001 Rev. 002 page 13 of 23
Laboratorians should use the following method when calculating workload:
All slides with Fields of View (FOV) only review count as 0.5 or ½ slide
All slides with full manual review (FMR) using the Autoscan feature count as 1 slide (as mandated by CLIA’88 for
manual screening)
Then, slides with both FOV and FMR count as 1.5 or 1½ slides
Use these values to count workload, not exceeding the CLIA maximum limit of 100 slides in no less than an 8-hour
day.
FMR = 1 slide
FOV = 0.5 slide
FMR + FOV = 1.5 slides
Upper Limit = 100 slides
The ThinPrep
Screening 22 Fields of View
Full manual slide review using the Autoscan feature
Review clinical history
Record results and triage appropriately
An example of workload scenario for ThinPrep Pap slides using the ThinPrep Imaging System:
100 FOV review only = 50 slides (100 x 0.5 = 50)
30 FOV review + FMR = 45 slides (30 x 1.5 = 45)
Total number of slides screened = 95 (50 FOV only and 45 FOV + FMR)
Note: ALL laboratories should have a clear standard operation procedure for documentation of their method of workload
counting and for establishing workload limits.
It is the responsibility of the Technical Supervisor to evaluate and set workload limits for individual cytotechnologists
based on laboratory clinical performance.
According to CLIA ’88, these workload limits should be reassessed every six months.
®
Imaging System limit of 100 slides in an 8-hour workday includes the following:
For less than an 8-hour workday, the following formula must be applied to determine the
maximum number of slides to be reviewed during that workday:
The manual workload limit does not supercede the CLIA requirement of 100 slides in a 24-hour
period in no less than an 8-hour day. Manual review includes the following types of slides:
Slides reviewed on the ThinPrep Imaging System using the Autoscan feature
Slides reviewed without the ThinPrep Imaging System
Non–gynecologic slides.
When conducting manual review, refer to the CLIA requirements for calculating workload limits.
G.6 THINPREP IMAGING SYSTEM USE WITH THINPREP 5000 PROCESSOR
A study was conducted to estimate the Positive Percent Agreement (PPA) and Negative Percent
Agreement (NPA) for Imager-assisted review as compared with manual review of specimens
processed on the ThinPrep 5000 processor.
8
100
MAN-03938-001 Rev. 002 page 14 of 23
Clinical Study Design
The study was a prospective, multi-center, blinded evaluation of ThinPrep slides of known
diagnoses generated from residual cytological specimens which were prepared, reviewed and
adjudicated in a previous study.
One thousand two hundred sixty (1260) slides were prepared on a ThinPrep 5000 processor and
were reviewed independently by a Cytotechnologist and confirmed by a Pathologist. All cytologic
diagnoses were determined in accordance with the Bethesda System 2001 c riteria for all slides
study was conducted at Hologic, Inc., Marlborough, MA and at two external laboratories in the
United States.
Table 16: Laboratory Imager-Assisted Review Diagnosis vs. Laboratory Manual Review
Diagnosis by one Pair of Cytotechnologist/Pathologist (Combined Sites)
Lab
ImagerAssisted
Review
Diagnosis
UNSAT 30 10 2 0 1 0 0 0 43
NILM 10 620 36 1 5 5 3 1 681
ASC-US 3 40 35 10 8 1 2 0 99
AGUS 0 10 28 127 8 0 8 0 181
LSIL 0 4 9 4 14 2 13 0 46
ASC-H 2 2 1 0 1 3 1 2 12
HSIL 1 3 6 15 24 2 111 5 167
Cancer 1 0 0 0 1 1 7 21 31
Total 47 689 117 157 62 14 145 29 1260
UNSAT NILM ASC-US AGUS LSIL ASC-H HSIL Cancer Total
Lab Manual Review Diagnosis
1
. The
Reference Diagnosis by Adjudication Review
All slides were subject to an adjudication review. Adjudication was done at a facility that was not
one of the study sites conducting the study. Slides for adjudication were even ly divided between
three (3) adjudication panels each consisting of one (1) Cytotechnologist and three (3) independent
Pathologists. Each adjudicatio n pa nel was bli nde d t o the ori ginal revi ew di agn osis for al l slides a nd
each independent Pathologist within each panel was also blinded to other adjudicator’s diagnoses
for all slides. Adjudication consensus agreement was obtained for each slide reviewed. Consensus
agreement was achieved when at least two (2) of the three (3) Pathologists from a panel rendered an
identical diagnosis. In cases where consensus agreement was not achieved the panel members were
brought together at a multi-head microscope to review the slides together and come to a consensus
diagnosis.
In the study, there were 18 Cancer, 92 HSIL, 37 ASC-H, 180 LSI L, 18 AGUS, 122 ASC-US, 770
NILM, and 23 UNSAT specimens. Clinical sensitivity and specificity (e.g., with reference to a
histological diagnosis) cannot be measured in this study which relied on cytological examination
alone. Instead, laboratory positive and negative diagnoses by both methods, Imager-assisted and
manual review, for the specimens with Reference Diagnosis of ASC-US+ (combined ASC-US,
AGUS, LSIL, ASC-H, HSIL, and Cancer), LSIL+ (combined LSIL, ASC-H, HSIL, and Cancer),
ASC-H+ (combined ASC-H, HSIL, and Cancer) and HSIL+ (combined HSIL and Cancer) were
compared.
MAN-03938-001 Rev. 002 page 15 of 23
Clinical Study Results
Tables 17 through 20 present the comparison of Laboratory true positive and negative rates for
ASC-US+, LSIL+, ASC-H+, and HSIL+.
Table 17: Laboratory Imager-Assisted Review Results vs. Laboratory Manual Review Results
for the Specimens with Reference Diagnosis of ASC-US+
In the study, there were 467 specimens with Reference Diagnosis of ASC-US+ (combined ASC-US, AGUS, LSIL, ASC-H,
HSIL, and Cancer) and 770 specimens with Reference Diagnosis of NILM.
In this table, “Positive” means ASC-US+ or UNSAT, and “Negative” means NILM. All percentages are rounded to the
nearest 0.1%.
ASC-US+ Positive Percent Agreement Negative Percent Agreement
Lab CT/
Pathologist
#1
#2
#3
Combined
Imager-Assisted Manual Difference Imager-Assisted Manual Difference
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
93.8% 95.1% -1.3% 84.4% 81.9% 2.5%
(287/306) (291/306) (-4/306) (434/514) (421/514) (13/514)
(90.5% to 96.0%) (92.1% to 97.0%) (-4.2% to 1.5%) (81.0% to 87.3%) (78.3% to 85.0%) (-0.2% to 5.3%)
91.6% 92.3% -0.6% 84.8% 85.2% -0.4%
(428/467) (431/467) (-3/467) (653/770) (656/770) (-3/770)
(88.8% to 93.8%) (89.5% to 94.4%) (-3.3% to 1.9%) (82.1% to 87.2%) (82.5% to 87.5%) (-2.9% to 2.1%)
91.9% 91.4% 0.4% 83.0% 83.4% -0.4%
(429/467) (427/467) (2/467) (639/770) (642/770) (-3/770)
(89.0% to 94.0%) (88.5% to 93.6%) (-2.1% to 3.0%) (80.2% to 85.5%) (80.6% to 85.8%) (-2.9% to 2.1%)
92.3% 92.7% -0.4% 84.0% 83.7% 0.3%
(1144/1240) (1149/1240) (-5/1240) (1726/2054) (1719/2054) (7/2054)
(90.6% to 93.6%) (91.1% to 94.0%) (-1.9% to 1.1%) (82.4% to 85.6%) (82.0% to 85.2%) (-1.1% to 1.8%)
MAN-03938-001 Rev. 002 page 16 of 23
Table 18: Laboratory Imager-Assisted Review Results vs. Laboratory Manual Review Results
for the Specimens with Reference Diagnosis of LSIL+
In the study, there were 327 specimens with Reference Diagnosis of LSIL+ (combined LSIL, ASC-H, HSIL, and Cancer)
and 910 specimens with Reference Diagnosis of (combined NILM, ASC-US, and AGUS).
In this table, “Positive” means LSIL+ or UNSAT, and “Negative” means NILM or ASC-US/AGUS. All percentages are
rounded to the nearest 0.1%.
LSIL+
Lab CT/
Pathologist
#1
#2
#3
Combined
Imager-Assisted Manual Difference Imager-Assisted Manual Difference
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
93.9% 90.0% 3.9% 86.1% 85.3% 0.8%
(215/229) (206/229) (9/229) (509/591) (504/591) (5/591)
(90.0% to 96.3%) (85.4% to 93.2%) (-0.5% to 8.5%) (83.1% to 88.7%) (82.2% to 87.9%) (-1.7% to 3.5%)
85.0% 88.1% -3.1% 87.4% 87.7% -0.3%
(278/327) (288/327) (-10/327) (795/910) (798/910) (-3/910)
(80.7% to 88.5%) (84.1% to 91.2%) (-7.0% to 0.8%) (85.0% to 89.4%) (85.4% to 89.7%) (-2.3% to 1.6%)
93.9% 87.5% 6.4% 84.3% 84.6% -0.3%
(307/327) (286/327) (21/327) (767/910) (770/910) (-3/910)
(90.7% to 96.0%) (83.4% to 90.6%) (3.2% to 10.0%) (81.8% to 86.5%) (82.1% to 86.8%) (-2.4% to 1.7%)
90.6% 88.3% 2.3% 85.9% 85.9% 0.0%
(800/883) (780/883) (20/883) (2071/2411) (2072/2411) (-1/2411)
(88.5% to 92.4%) (86.0% to 90.3%) (0.1% to 4.5%) (84.5% to 87.2%) (84.5% to 87.3%) (-1.3% to 1.2%)
Positive Percent Agreement Negative Percent Agreement
MAN-03938-001 Rev. 002 page 17 of 23
Table 19: Laboratory Imager-Assisted Review Results vs. Laboratory Manual Review Results
for the Specimens with Reference Diagnosis of ASC-H+
In the study, there were 147 specimens with Reference Diagnosis of ASC-H+ (combined ASC-H, HSIL, and Cancer) and
1,090 specimens with Reference Diagnosis of (combined NILM, ASC-US/AGUS, and LSIL).
In this table, “Positive” means ASC-H+ or UNSAT, and “Negative” means NILM, ASC-US/AGUS, or LSIL. All
percentages are rounded to the nearest 0.1%.
ASC-H+
Lab CT/
Pathologist
#1
#2
#3
Combined
Imaged Manual Difference Imaged Manual Difference
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
93.7% 88.3% 5.4% 86.7% 86.7% 0.0%
(104/111) (98/111) (6/111) (615/709) (615/709) (0/709)
(87.6% to 96.9%) (81.0% to 93.0%) (-0.6% to 12.0%) (84.0% to 89.0%) (84.0% to 89.0%) (-2.2% to 2.2%)
86.4% 86.4% 0.0% 89.4% 89.4% -0.1%
(127/147) (127/147) (0/147) (974/1090) (975/1090) (-1/1090)
(79.9% to 91.0%) (79.9% to 91.0%) (-6.8% to 6.8%) (87.4% to 91.1%) (87.5% to 91.1%) (-1.8% to 1.6%)
95.2% 89.8% 5.4% 88.2% 87.4% 0.7%
(140/147) (132/147) (8/147) (961/1090) (953/1090) (8/1090)
(90.5% to 97.7%) (83.8% to 93.7%) (-0.1% to 11.4%) (86.1% to 90.0%) (85.3% to 89.3%) (-1.0% to 2.5%)
91.6% 88.1% 3.5% 88.3% 88.0% 0.2%
(371/405) (357/405) (14/405) (2550/2889) (2543/2889) (7/2889)
(88.5% to 93.9%) (84.6% to 90.9%) (0.0% to 7.0%) (87.0% to 89.4%) (86.8% to 89.2%) (-0.8% to 1.3%)
Positive Percent Agreement Negative Percent Agreement
MAN-03938-001 Rev. 002 page 18 of 23
HSIL+
Lab CT/
Pathologist
#1
#2
#3
Combined
Table 20: Laboratory Imager-Assisted Review Results vs. Laboratory Manual Review Results
for the Specimens with Reference Diagnosis of HSIL+
In the study, there were 110 specimens with Reference Diagnosis of HSIL+ (combined HSIL and Cancer) and 1,127
specimens with Reference Diagnosis of (combined NILM, ASC-US/AGUS, LSIL, and ASC-H).
In this table, “Positive” means HSIL+ or UNSAT, and “Negative” means NILM, ASC-US/AGUS, LSIL, or ASC-H. All
percentages are rounded to the nearest 0.1%.
Positive Percent Agreement Negative Percent Agreement
Imaged Manual Difference Imaged Manual Difference
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
90.7% 80.2% 10.5% 86.8% 89.1% -2.3%
(78/86) (69/86) (9/86) (637/734) (654/734) (-17/734)
(82.7% to 95.2%) (70.6% to 87.3%) (2.9% to 18.8%) (84.1% to 89.0%) (86.6% to 91.2%) (-4.6% to -0.1%)
80.9% 74.5% 6.4% 92.1% 92.3% -0.2%
(89/110) (82/110) (7/110) (1038/1127) (1040/1127) (-2/1127)
(72.6% to 87.2%) (65.7% to 81.8%) (-2.0% to 14.7%) (90.4% to 93.5%) (90.6% to 93.7%) (-1.7% to 1.4%)
90.9% 82.7% 8.2% 89.0% 89.7% -0.7%
(100/110) (91/110) (9/110) (1003/1127) (1011/1127) (-8/1127)
(84.1% to 95.0%) (74.6% to 88.7%) (0.7% to 16.0%) (87.0% to 90.7%) (87.8% to 91.3%) (-2.4% to 0.9%)
87.3% 79.1% 8.2% 89.6% 90.5% -0.9%
(267/306) (242/306) (25/306) (2678/2988) (2705/2988) (-27/2988)
(83.1% to 90.5%) (74.2% to 83.3%) (3.7% to 12.7%) (88.5% to 90.7%) (89.4% to 91.5%) (-1.9% to 0.1%)
In the study, there were 1.83% (23/1260) ThinPrep 5000 slides with UNSAT results by
Adjudication.
MAN-03938-001 Rev. 002 page 19 of 23
ImagerAssisted
Review
Three lab
CTs have
read the
same slide
Agreement among Laboratory Cytotechnologists/Pathologists
The following tables indicate the extent to which the laboratory Cytotechnologists/Pathologists at a
given site agreed amongst t hemselves on the diagno sis, comparing the Im ager-assisted review to the
manual review. Tables are provided for ASC-US+ and ASC-H+. Note that since one site had only
two CT/Pathologist pairs, the three-way agreement analysis is available for just two sites, with 840
total specimens.
In Table 21 for ASC-H+, the number of specimens is shown for which various levels of agreement
among the CTs occurred. Either all three CTs rated the slide as positive (ASC-H+), two out of three
rated it positive, one out of three, or none of them.
Table 21: Laboratory Cytotechnologist/Pathologist Agreement, All Results, ASC-H+
ASC-H+
Three CTs had
ASC-H+
Two CTs had ASC-H+
and one had <ASC-H
One CT had ASC-H+
and two had <ASC-H
Three lab CTs have read the same slide
Three CTs
had
ASC-H+
91 23 8 0 122
12 21 7 8 48
3 12 16 11 42
Manual Review
Two CTs had
ASC-H+
& one had
<ASC-H
One CT had
ASC-H+
& two had
<ASC-H
Three
CTs had
<ASC-H
Totals
Three CTs had
<ASC-H
Totals
ASC-H+
ImagerAssisted
Review
Three lab
CTs have
read the
same slide
Three or two CTs had
ASC-H+
Three or two CTs had
<ASC-H
Totals
0 2 22 604 628
106 58 53 623 840
Manual Review
Three lab CTs have read the same slide
Three or two CTs
had ASC-H+
147 23 170
17 653 670
164 676 840
Three or two CTs
had <ASC-H
Totals
MAN-03938-001 Rev. 002 page 20 of 23
The rate of agreement between the Imager-assisted review result an d the m anual revi ew result from
the previous table is presented below. PPA is the positive percent agreement, percent of specimens
of ASC-H+ diagnosis with Imager-assisted review by a majority of laboratory CT/Pathologists
among all specimens of ASC-H+ diagnosis with manual review by a majority of laboratory
CT/Pathologists. NPA is the negative percent agreement, percent of specimens of <ASC-H
diagnosis with Imager-assisted review by a majority of laboratory CT/Pathologists among all
specimens of <ASC-H diagnosis with manual review by a majority of laboratory CT/Pathologists.
Table 22: Rate of CT/Pathologist Agreement, ASC-H+
ASC-H+
PPA
NPA
89.0% (147/164) (83.3% to 92.9%)
96.6%
(653/676)
(95.0% to 97.7%)
In Table 23 for ASCUS+, the number of specimens is shown for which various levels of agreement
among the CTs occurred. Either all three CTs rated the slide as positive (ASCUS+), two out of three
rated it positive, one out of three, or none of them.
Table 23: CT Agreement, All Results, ASCUS+
Manual Review
Two CTs had
ASCUS+ &
one had
<ASCUS
One CT had
ASCUS+ &
two had
<ASCUS
ImagerAssisted
Review
Three lab CTs
have read the
same slide
ASCUS+
Three CTs had
ASCUS+
Two CTs had
ASCUS+ and one had
<ASCUS
One CT had ASCUS+
and two had <ASCUS
Three CTs had
<ASCUS
Three lab CTs have read the same slide
Three CTs
had
ASCUS+
272 22 8 0 302
15 16 6 7 44
7 10 24 38 79
0 5 28 382 415
Three CTs
had
<ASCUS
Totals
Totals
ASCUS+
ImagerAssisted
Review
Three lab
CTs have
read the
same slide
Three or two CTs had
ASCUS+
Three or two CTs had
<ASCUS
Totals 347 493 840
294 53 66 427 840
Manual Review
Three lab CTs have read the same slide
Three or two CTs
had ASCUS+
325 21 346
472 494
22
Three or two CTs
had <ASCUS
MAN-03938-001 Rev. 002 page 21 of 23
Totals
The rate of agreement between the Imager-assisted review result an d the m anual revi ew result from
the previous table is presented below. PPA is the positive percent agreement, percent of specimens
of ASCUS+ diagnosis with Imager-assisted review by a majority of laboratory CT/Pathologists
among all specimens of ASCUS+ diagnosis with manual review by a majority of laboratory
CT/Pathologists. NPA is the negative percent agreement, percent of specimens of <ASCUS
diagnosis with Imager-assisted review by a majority of laboratory CT/Pathologists among all
specimens of <ASCUS diagnosis with manual review by a majority of laboratory CT/Pathologists.
Table 24: Rate of CT Agreement, ASCUS+
ASCUS+
PPA
NPA
93.7% (325/347) (90.6% to 95.8%)
95.7% (472/493) (93.6% to 97.2%)
H. Clinical Investigation Conclusions
For all sites combined for ASCUS+, the improvement in sensitivity of the Imager Review
method over the Manual Review method is statistically significant. This increase is 6.4%
with a 95% confidence interval of 2.6% to 10.0% for all sites combined. The differences
in sensitivity varied among the sites from –2.8% to +14.4%. For LSIL+ and HSIL+ the
sensitivity of the Imager Review method is equivalent to the Manual Review method.
For all sites combined for HSIL+, the improvement in specificity of the Imager Review
method over the Manual Review method is statistically significant. This increase is 0.2%
with a 95% confidence interval of 0.06% to 0.4% for all sites combined. The differences
in specificity varied among the sites from –0.1% to +0.7%. For ASCUS+ and LSIL+ the
specificity of the Imager Review method is equivalent to the Manual Review method.
Specimen adequacy can be determined using the method described in Bethesda System
2001 or by having the Cytotechnologist count the cells in the 22 fields of view presented
by the Imager.
The workload limit for the ThinPrep Imaging System has be en est a bl is hed at 200 slides in
no less than an 8-hour workday. This workload limit of 200 slides includes the time spent
for manual review of slides that is not to exceed 100 slides in an 8 hour workday.
For these clinical sites and these study populations, the data from the clinical trial and clinical
support studies demonstrate that the use of the ThinPrep Imaging System to assist during primary
screening of ThinPrep Pap Test slides for all cytologic interpretations, as defined by the Bethesda
System, is safe and effective for the detection of cervical abnormalities.
Performance may vary from site to site as a result of differences in patient populations and reading
practices. As a result each laboratory using t his device s houl d employ qualit y assurance a nd contr ol
systems to ensure proper use and selection of appropriate workload limits.
MAN-03938-001 Rev. 002 page 22 of 23
I. Bibliography
1. Solomon D., Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, Raab S, Sherman M, Wilbur
D, Wright T, Young N, for the Forum Group Members and the 2001 Bethesda Workshop. The
2001 Bethesda System Terminology for Reporting Results of Cervical Cancer. JAMA.
2002;287:2114-2119.
2. Kurman RJ, Solomon D. The Bethesda System for Reporting Cervical/Vagin al Cytologic
Diagnoses. Springer-Verlag 1994.
3. Schafer, J.L. Multiple imputation: a primer. Statistical Methods in Medical Research, 1999, 8:3-
15.
4. Nationa l Cancer Institute. SEER Cancer Statistics Review 1973-1998. Available at:
http://www.seer.cancer.gov. Accessed February 2002.
Hologic, Inc.
250 Campus Drive
Marlborough, MA 01752 USA
1-800- 442-9892
www. hologic.com
© 2015 Hologic, Inc. All rights reserved.
MAN-03938-001 Rev. 002 page 23 of 23
AW-12515-001 Rev. 001
Table of Contents
Table of Contents
Table of Contents
Chapter One
INTRODUCTION
SECTION A:
SECTION B:
SECTION C:
SECTION D:
SECTION E:
SECTION F:
SECTION G:
Chapter Two
INSTALLATION
SECTION A:
SECTION B:
SECTION C:
SECTION D:
SECTION E:
SECTION F:
SECTION G:
Overview and Function of the Review Scope 1.1
The ThinPrep® Imaging System Process 1.4
Specimen Preparation and Processing 1.6
Review Scope Technical Specifications 1.6
Internal Quality Control 1.13
Review Scope Hazards 1.13
Disposal 1.18
General 2.1
Action Upon Delivery 2.1
Preparation Prior to Installation 2.1
Moving the Review Scope 2.2
Connecting Review Scope Components 2.3
Power On the Review Scope 2.7
Storage and Handling - Post Installation 2.10
Chapter Three
OPERATION OF THE REVIEW SCOPE
SECTION A:
SECTION B:
SECTION C:
SECTION D:
SECTION E:
SECTION F:
Overview 3.1
Materials Required Prior to Operation 3.5
Auto Review 3.6
Subsequent Review 3.16
Manual Slide Review 3.18
Shutting Down the Review Scope 3.24
Review Scope Operator’s Manual
i
Chapter Four
OPERATION OF THE SOFTWARE MENU
SECTION A:
SECTION B:
SECTION C:
SECTION D:
SECTION E:
SECTION F:
SECTION G:
Introduction 4.1
Menu Option 1 Login/Logout 4.3
Menu Option 2 Joystick Calibration 4.4
Menu Option 3 Setup Marker 4.6
Menu Option 4 Preferences 4.13
Menu Option 5 Open Error Log 4.27
Menu Option 6 Usage Count 4.28
ThinPrep Review Scope Preferences Worksheet
Chapter Five
REVIEW SCOPE MAINTENANCE
SECTION A:
SECTION B:
SECTION C:
SECTION D:
SECTION E:
Daily 5.1
General Cleaning 5.1
Replacing the Illuminator Light Bulb 5.2
Replacing the Fuses 5.5
Koehler Alignment 5.8
Chapter Six
TROUBLESHOOTING
SECTION A:
SECTION B:
SECTION C:
SECTION D:
Chapter Seven
DEFINITIONS AND ABBREVIATIONS 7.1
Chapter Eight
SERVICE INFORMATION 8.1
Chapter Nine
ORDERING INFORMATION 9.1
INDEX
ii
Review Scope Operator’s Manual
Operation Errors 6.1
User-Correctable Errors 6.4
Recoverable System Errors 6.13
Miscellaneous 6.13
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