Recent Findings on Test Performance

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Recent Findings on Test Performance

• Brian P. Mulhall, MD MPH
• Walter Reed Army Medical Center

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Colorectal Cancer ScreeningViable Tests

• FOBT
• Rehydrated and unrehydrated
• Immunochemical FOBT
• Barium Enema
• Flexible Sigmoidoscopy
• Colonoscopy
• Virtual Colonoscopy
• Stool DNA

The Past
The Present.
The Future?
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Fecal Occult Blood Tests
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Fecal Occult Blood Tests

• FOBTs
• GUAIAC-based
• Hemoccult II
• Hemoccult SENSA
• Fecatwin S
• Coloscreen III/VPI
• Hemoccult Wipe
• Immunochemical tests
• FECA-EIA
• Monohaem
• HemeSelect
• HemoQuant

n81
Gopalswamy, N., et al. Arch Fam Med 3 1043,
1994.
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Test PerformanceFOBTs

• GUAIAC-based
• Hemoccult II
• Hemoccult SENSA
• Fecatwin S
• Coloscreen III/VPI
• Hemoccult Wipe
• Hemofec
• Hemopreuve
• Unrehydrated/Rehydrated

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Test PerformanceImmunochemical FOBTs

• IFOBTs
• FECA-EIA
• Hemolex
• Monohaem
• HemeSelect
• HemoQuant
• Hemoblot
• BM-test Colon
• Immudia-HemSp
• OC-hemodia
• Immunohemostick
• RPHA
• Fecal calprotectin
• Magstream 1000
• FlexSure OBT

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FOBT vs. IFOBT

• Large VA-based population study
• Varied risk for CRC, 98 male
• IFOBT (FlexSure OBT) vs. FOBT (HemoccultSENSA)
• 2965 tests ordered each 1410/1369 returned
• 48 return rate
• 66 positive results referred for colonoscopy
  (50 completed)
  
• Test Performance
• PPV Adenoma PPV Adenoma 1 cm or Cancer
• IFOBT ? 58 17
• FOBT ? 59 30

Ko, C.W., et al. FOBT in a General Medicine
Clinic Comparison of GUAIAC and IFOBT. Am J Med,
115 111-114, 2003.
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Barium Enema
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Test PerformanceBarium Enema

• Infrequently used in practice
• Limited data on impact on outcomes
• Varied studies
• Symptomatic or high-risk populations (Sensitivity
  ? 85-90)
  
• Work-up bias
• Retrospective cohort studies (Sensitivity ?
  70-96)
  
• Biased
• Surveillance populations (Sensitivity ? 30-81
  NPS Sens 50 polyps 1 cm)
  
• Selection bias
• Tagged polyp study (specificity ? 96-98 for
  polyps 7-10 mm or CA)
  
• Data for hyperplastic versus adenomatous polyps
  not reported
  

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Endoscopy
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Test PerformanceFlexible Sigmoidoscopy

• An accepted standard for CRC screening
• Permits detection and removal of distal polyps
• Insertion beyond the sigmoid in
• Proximal lesions may be missed
• In average-risk patients with distal adenomas
• Half had lesions beyond the reach of the
  sigmoidoscope
  
• Autopsy studies show 50-70 adenomas are
  proximal
  
• Overall sensitivity ? 60-70
• Sensitivity for distal lesions ? 85-95
• Specificity ? 85-98

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Test PerformanceColonoscopy

• The Gold Standard for diagnosing polyps and
  CRC
  
• Visualizes the entire colon
• Examination completed ? 80-98
• Allows identification, removal of culprit
  lesions
  
• Prevents 60-80 colorectal cancers
• Sensitivity
• Cancer ? 79-100
• Polyps ? 73-100 (85 polyps 5 mm 92 7 mm)
• Miss rate for polyps 8 mm ? 0-26 Polyps mm ? 15-30
  
• Specificity
• Assumed to be 100
• Likely in the range of 90-95

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Stool DNA
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(No Transcript)
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Test PerformanceStool DNA

• About 50 of CRCs have K-ras mutations
• False positives in IBD and lymphocytic colitis
• New multi-target assays have been developed
• Uses K-ras, APC, p53, BAT-26, L-DNA/DIA
• Improved test performance over single mutations
• Sensitivity in high-risk groups
• Adenomas ? 47-82
• Cancers ? 64-91
• Screening populations (n2,507)
• Sensitivity for advanced adenomas ? 15
• Specificity in patients with polyps ? 95

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Test PerformanceVirtual Colonoscopy

• Evolving technology
• Wide range of results
• 2-D vs. 3-D
• Software and hardware
• Radiologist experience
• Prevalence of population
• Sensitivity for polyps
• 10 mm ? 32-96
• 6-9 mm ? 41-94
• Specificity for polyps
• 10 mm ? 74-98
• 6-9 mm ? 63-95

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Virtual Colonoscopy
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Virtual Colonoscopy StudiesAll with n 100
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V.C. Study Results Per Patient Analysis
(1) 1 reader (2) 2 readers (3) 3 readers
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The Pickhardt Study -Methods

• Multi-center Enrollment
• Adults ages 50-79
• Adults with FH CRC ages 40-79
• Preparation
• Fleet PhosphoSoda Bisacodyl
• 500 ml barium with clear diet
• Solid-stool tagging
• 120 mL of diatrozoate meglumine and diatrozoate
  sodium
  
• Liquid opacification

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The Pickhardt Study Diagnostic Methods

• Optical Colonoscopy
• Standard videoendoscope
• 17 experienced endoscopists
• 14 GI, 3 GS
• Polyps measured by calibrated linear probe
• Segmental unblinding
• Polyps resected
• Sent for pathology
• Procedural times recorded
• Questionnaires provided

• Virtual Colonoscopy
• Rectal catheter
• Patient-controlled insufflation
• Breath-holding
• Supine and prone
• GE Lightspeed or Ultra CT
• Reconstruction interval 1 mm
• Viatronix 3D Colon 1.2
• Virtual fly-through
• Correlation with 2-D images
• Polyps measured by electronic calipers
• Extra-colonic findings recorded
• Analyzed by experienced radiologists

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The Pickhardt Study -Statistical Analysis

• OC Reference Standard
• Primary outcome
• Polyps 6 mm
• Advanced neoplasia
• Polyps 10 mm
• HGD, TV, or cancer
• Polyp Matching VC/OC
• True positive
• Same/adjacent segment
• Diameters equal /- 50
• True positive by size
• Polyp of size on VC OC

• Analysis using
• McNemars test
• Fishers exact test
• Chi-square tests
• Paired t-tests
• Interobserver reliability
• 100 random VCs
• 2nd read by blinded radiologist
• Kappa defined

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Pickhardt Results

• 1233/1253 patients completed VC/OC
• 1201 average risk
• Adenomas
• 10 mm? 3.9
• 8 mm ? 6.7
• 6 mm ? 13.6
• Malignant ? 0.4
• Advanced polyps

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Pickhardt Results Test Performance

• Polyps on VC not OC
• 55 polyps
• 21 TAs 6 mm
• Advanced Neoplasms
• Sensitivity
• VC ? 91.5
• OC ? 88.1
• Colon Cancer
• Sensitivity
• VC ? 100 (2/2)
• OC ? 50 (1/2)

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Pickhardt Results

• Extra-colonic findings (rates are half of
  previous reports)
  
• Potentially high clinical importance ? 4.5
• 7/56 had extra-colonic cancer or AAA (12.5)
• Potentially moderate clinical importance ? 13.5
• Nephrolithiasis (7.9) or cholelithiasis (5.6)
• Procedural time
• VC ? 14.1 minutes (in CT suite)
• OC ? 31.5 minutes (64.4 additional min.s in
  recovery)
  
• Satisfaction (81.5 questionnaires returned)
• Greater discomfort VC 54.3 vs. OC 38.1
• More acceptable(convenience) VC 68.3 vs. OC
  24.1

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Pickhardt ResultsSummary Statistics

• VC for polyps 8 mm
• Sensitivity Specificity 90
• 1 in 6 patients will get OC
• Kappa 0.75
• VC OC for CT/radiologist time
• Quicker for patients
• VC less comfortable than OC
• But more acceptable
• Bottom-line
• VC better than OC for detection of adenomas

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Pickhardt Study Questions/Issues

• What is the gold standard in this study?
• OC was the reference standard
• But sensitivity defined for VC and OC. Perhaps
  this is reasonable, but
  
• Proceduralists ? Staff radiologists vs.
  Staff/Fellows GI/Surgeons
  
• What about data for hyperplastic polyps?
• Specificity of VC for any polyps
• Polyps 10 mm ? 97.4
• Polyps 8 mm ? 95.0
• Polyps 6 mm ? 84.5
• What about small advanced polyps?
• Only 0.1 polyps
• But what about with 6 or 7 mm polyps?
• Test positive rate at 8 mm is 13.5 (1 in 6 get
  colonoscopy)
  
• At 6 mm, 1 in every 3 patients get colonoscopy
  (where spec 80)

VC HPs 5-8 mm would get VC q 2-3 years
All OC HPs would get next OC at 10 years
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Test PerformanceOther Studies

• FDG-PET
• Dark lumen MR colography
• Chromoendoscopy

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Test PerformanceThe Bottom-Line
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Test PerformanceThe Bottom-Line
40 100
50 95
80 100
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Summary Comments

• No test has been established as the Gold
  Standard
  
• Tests
• FOBTs and IFOBTs
• Wide range of sensitivity and specificity
• Lower sensitivity, but has demonstrated benefit
• Barium Enema
• Has acceptable sensitivity and specificity
• Suffers from limited usage, inadequate study,
  inconvenience
  
• Sigmoidoscopy
• Has acceptable sensitivity and specificity
• Limited exam of colon, usage/training suffers
  colonoscopys role

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Summary Comments

• Tests
• Colonoscopy
• Has high sensitivity and specificity (?)
• Miss rate, incomplete examinations and
  complications
  
• Virtual Colonoscopy
• Has a range of sensitivity and specificity (high
  specificity)
  
• Hard-/Software, inter-observer reliability,
  inability for intervention
  
• Stool DNA
• Has a range of sensitivity, specificity
• Limited number of studies, assay dependent, lab
  dependent

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BIBLIOGRAPHY

• See References in Notes View