Critical appraisal:Shi XY, Bhagwandeen B, Leong AS 2008

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Critical Appraisal

Article being appraised

Shi XY, Bhagwandeen B, Leong AS. CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus. Am J Clin Pathol 2008 Apr;129(4):571-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18343784.


Applicable clinical question

Key Facts

Study Design

diagnostic accuracy study

Number of Patients enrolled:

Not applicable

Number of Patients evaluated:

Not applicable

Number of samples:

128


Includes an economic evaluation

no

Evidence ratings

Level of evidence

III-3

Risk of bias
At risk of bias Comments: Please replace this text and include any additional comments in regards to your quality rating

Risk of bias assessment: diagnostic accuracy study

Patient Selection
Prior tests and any referral filters
Biopsy and resection specimens from endoscopy performed from 1999 to 2006, were obtained from the database of the Division of Anatomical Pathology, Hunter Area Pathology Service, Newcastle, Australia. Clinical data and pathological slides were reviewed in all cases. Morphologically normal gastric mucosa control samples were selected from patients unassociated with GERD and showed no microscopic evidence of inflammation or IM.
Condition that defined entry into study
128 esophageal biopsy and resection specimens were obtained, including 108 BO samples (94 with confirmed goblets cells, 14 with SSBO diagnosis but no goblet cells in the sections studied) and 20 control samples of morphologically normal gastric fundic mucosa.
Setting
A single centre study performed using samples obtained from the Division of Anatomical Pathology, Hunter Area Pathology Service, Newcastle, Australia.
Was a diagnostic case-control design avoided?
Yes
Consecutive or random sample?
Unclear
Did the study avoid inappropriate exclusions?
Yes
Reasons
A single section was excluded as a result of insufficient tissue for staining.
If comparing more than one index test was the design fully paired or paired randomly?
Not applicable
If a paired randomised design was used, was allocation to groups concealed and was the generation of allocation sequence adequate?
Not applicable
What is the risk that the selection of participants introduced bias?
Unclear
Comments
It was not stated whether each biopsy came from a unique patient or whether several biopsies were taken from a single patient. The patient selection was designed to address the question of whether CDX2 and Villin were valuable markers for the identification of intestinal metaplasia however the clinical appropriateness of the control group is debatable.
Index test 1
Describe index test and how it was conducted and interpreted
Index test was immunohistochemical staining of biopsy sections for CDX2 and Villin,. HepPar-1 and cytokeratin-7 (CK7) immunostaining was also performed as a comparison back to previous study results. All immunohistochemical stains were separately evaluated by two pathologists. Negative control samples omitted the primary antibody (using 5% goat serum as a substitute) and known positive tissues served as positive controls. Method of interpretation of staining was not stated.
Were the index test results interpreted without knowledge of the results of the reference standard?
Unclear
If a threshold was used, was it pre-specified?
Not applicable
If two tests are being compared, have they been assessed independently / blind to each other?
Not applicable
What is the risk that the conduct or interpretation of the index test introduced bias?
Low
Comments
Two independent pathologists were used to evaluate results of the index test.
Index test 2
Describe index test and how it was conducted and interpreted, if applicable
Not applicable
Were the index test results interpreted without knowledge of the results of the reference standard?
Not applicable
If a threshold was used, was it pre-specified?
Not applicable
What is the risk that the conduct or interpretation of the index test introduced bias?
Not applicable
Comments
Not applicable
Reference Standard
Describe the reference standard and how it was conducted and interpreted
Reference standard was histological evalutation of H&E stained sections of FFPE tissue form biopsies taken during endoscopic examination. Alcian blue and periodic acid-Schiff (PAS) staining were used to confirm the presence of mucin-containing goblet cells.
Is the reference standard likely to correctly classify the target condition?
Yes
Were the reference standard results interpreted without knowedge of the results of the index test/s?
Yes
Was the reference test standard independent of the index test?
(i.e. the index test did not form part of the reference standard)
Yes
What is the risk that the reference standard, its conduct or interpretation introduced bias?
Low
Comments
The reference standard used here is the universally accepted method for diagnosis of Barrett’s oesophagus, with the additional PAS and Alcian blue staining to identify mucin-containing goblet cells.
Flow and timing
Describe any patients who did not receive the index test(s) and/or reference standard or who were excluded from the 2x2 table
All patients who received the index test also received the reference standard (with the exception of PAS and Alcian blue staining for the 20 normal gastric mucosa samples; these samples were still evaluated using the standard H&E staining).
Describe the time interval and any interventions between index test(s) and reference standard
Tissue samples for both the reference standard and index test were taken at a single endoscopy session, hence no intervention between index test and reference standard is possible.
If a predictive test (the reference standard is a later event that the test aims to predict) were any subsequent interventions between test and later event blind to test result?
Not applicable
Was there an appropriate interval between index test(s) and reference standard?
Yes
Did either all participants or a random sample of participants receive a reference standard test?
Yes
Did all patients receive the same reference standard irrespective of index test result?
Yes
Were all test results including unclear results reported?
Yes
Were all patients included in the analysis?
Yes
What is the risk that the patient flow introduced bias?
Low
Comments
Patient specimens were selected from a database and tissue blocks were accessed to obtain samples. No further interaction with patients was required.
Size of effect
5 Reason for decision: CDX2 and Villin staining was positive in 100% of the BO cases with confirmed goblet cells, and in none of the normal gastric mucosa samples. However in the non-goblet cell mucosa from patients with BO, the sensitivity was reduced to just 14% (CDX2) and 43% (Villin). In the cardiac type and fundic type mucosa associated with BO (occurring as separate pieces of tissue included in the single oesophageal sample); sensitivity of CDX2 was 34% and 0% respectively and sensitivity of Villin was 21% and 11% respectively. These sensitivity values indicate that CDX2 and Villin are a sensitive marker for goblet cell containing mucosa in a BO patient, but do not confirm the presence of BO if the sampling does not include goblet cells. To state 100% specificity for the test is misleading as control samples are normal fundic gastric samples (a site distant from the distal oesophagus where BO is detected).
Relevance of evidence
4 Additional comments: Provides evidence that CDX2 and Villin are senstitive markers for the presence of goblet cell containing intestinal metaplasia but not the nearby non-goblet cell columnar mucosa. The results do not support CDX2 and Villin overcoming the sampling issue associated diagnosis of BO (BO may be present, but if not correctly biopsied, may be missed). Testing showed HepPar-1 to have limited sensitivity and CK7 was not specific. Does not provide evidence that the test improves outcome for the patient.
Result of appraisal

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Completed by

Melissa Thomas


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Article
Shi XY, Bhagwandeen B, Leong AS. CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus. Am J Clin Pathol 2008 Apr;129(4):571-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18343784.
Assigned to
User:Reginald.lord
Topic area
Guidelines:Barrett's
Clinical question
Form
Form:Critical appraisal


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