The Tahoe Study:
Bias in interpretation of Pap tests
when HPV status is known
AT Moriarty, R Nayar, A Renshaw, N Thomas, R Souers
On behalf of the College of American Pathologists Cytopathology Committee
Conflict of interest
The authors have no conflict of interest to disclose.
The Tahoe Study: Introduction • Pap test performance successful
The Tahoe Study: Introduction • Pap test performance successful
• As the prevalence of disease drops test performance is important
The Tahoe Study: Introduction • Pap test performance successful
• As the prevalence of disease drops test performance is important
• Detect those with significant abnormalities
The Tahoe Study: Introduction • Pap test performance successful
• As the prevalence of disease drops test performance is important
• Detect those with significant abnormalities
• Avoid harm of follow up in those without disease
The Tahoe Study: Introduction • Pap test performance successful
• As the prevalence of disease drops test performance is important
• Detect those with significant abnormalities
• Avoid harm of follow up in those without disease
• Primary HPV screening sensitive, less specific
The Tahoe Study: Introduction • Pap test performance successful
• As the prevalence of disease drops test performance is important
• Detect those with significant abnormalities
• Avoid harm of follow up in those without disease
• Primary HPV screening sensitive, less specific
• Pap test as possible triage (reflex test)
The Tahoe Study: Introduction • Pap test performance successful
• As the prevalence of disease drops test performance is important
• Detect those with significant abnormalities
• Avoid harm of follow up in those without disease
• Primary HPV screening sensitive, less specific
• Pap as possible triage (reflex test)
• Will there be a bias if HPV status is known?
The Tahoe Study: Introduction • Use HPV positive/negative Pap slides for QA
The Tahoe Study: Introduction • Use of HPV positive negative slides for QA
• Enriched population of “high risk”
The Tahoe Study: Introduction • Use of HPV positive negative slides for QA
• Enriched population of “high risk”
• Independent results of Pap and HPV
The Tahoe Study: Introduction • Use of HPV positive negative slides for QA
• Enriched population of “high risk”
• Independent results of Pap and HPV
• Review morphology of negative cases
The Tahoe Study: Introduction • Use of HPV positive negative slides for QA
•
•
•
•
Enriched population of “high risk”
Independent results of Pap and HPV
Review morphology of negative cases
Epithelial cell abnormalities detected
The Tahoe Study: Introduction • Use of HPV positive negative slides for QA
•
•
•
•
Enriched population of “high risk”
Independent results of Pap and HPV
Review morphology of negative cases
Epithelial cell abnormalities detected
• Observation: Bias
The Tahoe Study: Materials
• 40 de‐identified cervical cytology slides
– Time period: 2009‐2010
– Originally all interpreted as NILM
– All had positive HRHPV co‐testing results
– Originally reviewed as part of QA program
– Randomly divided into 2 sets of 20
The Tahoe Study: Method
• 22 members of the CAP Cytopathology Resource Committee divided into 2 groups
– Age, specimen source given
– HPV status not revealed
– Interpretation choices: NILM, ASC‐US, LSIL, HSIL+
– Each group reviewed 2 sets of 20 slides each
1
2
The Tahoe Study: Method
• After completion of initial review
– Slides collected
– Sets of 20 slides re‐labeled as B sets
– Age, specimen source given
– HPV status revealed
– Interpretation choices: NILM, ASC‐US, LSIL, HSIL+
– Slide sets switched to avoid slide recall
2B
1B
The Tahoe Study: Method
• Differences in the responses between groups – 41 responses not available
– One observer failed to review both sets of slides
– One participant gave two responses for one slide
• Statistical analysis
– chi‐square
– Cochran‐Mantel‐Haenszel tests – .05 significance level The Tahoe Study: HPV bias
• No difference between observer groups (P=.41)
• Confirms randomization of groups
Response category
Group 1
Group 2
NILM
136
37.9%
176
36.7%
ASC‐US
91
25.3%
124
25.8%
LSIL
60
16.7%
99
20.6%
HSIL+ Total
72
359
20.1%
81
480
16.9%
The Tahoe Study: HPV bias
• HPV status not known
– more likely to identify the slides as (NILM) • Biased group
– more likely to identify (ECA) P<.001
Biased
Unbiased
General category response
NILM
131
31.3%
181
43.1%
ECA
228
68.7%
239
56.9%
Total
419
420
The Tahoe Study: HPV bias
• Increase in each ECA descriptive diagnostic category P=.002
Biased
Unbiased
Response
NILM
131
31.3%
181
43.1%
ASC‐US
114
27.2%
101
24.0%
LSIL
94
22.4%
65
15.5%
HSIL+ Total
80
419
19.1%
73
420
17.4%
The Tahoe Study: Conclusion
• HPV status creates a bias in interpretation of Pap tests. The Tahoe Study: Conclusion
• HPV status creates a bias in interpretation of Pap tests. • With the knowledge of a current positive HPV test, observers are more likely to report the Pap test as abnormal.
The Tahoe Study: Conclusion
• HPV status creates a bias in interpretation of Pap tests. • With the knowledge of a current positive HPV test, observers are more likely to report the Pap test as abnormal.
• With the knowledge of a current positive HPV test, observers report abnormalities across all categories of epithelial cell abnormality.
The Tahoe Study: Conclusion
• HPV status creates a bias in interpretation of Pap tests. • With the knowledge of a current positive HPV test, observers are more likely to report the Pap test as abnormal.
• With the knowledge of a current positive HPV test, observers report abnormalities across all categories of epithelial cell abnormality.
• If HPV status is known when interpreting a co‐test, the Pap test in a specimen with a positive HRHPV test may more likely be reported as abnormal.
The Tahoe Study: Conclusion
• If HPV testing is used as a primary screening test with Pap tests as a secondary (reflex test), it may be likely that the Pap test will be interpreted as abnormal as compared to when a Pap test is used as a primary screening test.
CAP Cytopathology Committee 2010
Ann T. Moriarty MD, Chair
Barbara Crothers, Vice Chair
Manon Auger, MD
Guliz A. Barkan, MD
Joel S. Bentz, MD
Christine Noga Booth, MD
Amy C. Clayton MD
Teresa M Darragh MD
Galen M Eversole MD
Andrew H Fischer MD
Mostafa M Fraig MD,
Michael Ross Henry MD
Lydia P Howell MD,
Walid E Khalbuss MD,PhD
CAP Staff
Andrew Hartley, CT(ASCP)
Nicole Thomas, MPH, CT(ASCP)
Rhona Souers, MS, Biostatistics
Roger Bert Lane MD
Rodolfo Laucirica MD
Ritu Nayar MD,
Malcolm Schinstine MD,PhD
Mary R Schwartz MD
Patricia G Wasserman MD
Barbara Anne Winkler MD
Maureen F Zakowski MD
Ly Ma MD
David C Wilbur MD,
Marilee M Means PhD SCT(ASCP)
Sue Zaleski CT(ASCP)
Rosemary H Tambouret MD
Mid America Clinical Lab Staff
Terry Arnold, CT(ASCP)
Lisa Gearries CT(ASCP)
The Tahoe Study: HPV bias
The Tahoe Study:
Bias in interpretation of Pap tests
when HPV status is known
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