Review for 10.1186/s12876-021-01998-w (2021)

Title: Diagnostic yield of esophagogastroduodenoscopy, colonoscopy, and small bowel
endoscopy in Thai adults with chronic diarrhea
Version: 1 Date: 30 May 2021
Reviewer's report:
Thank you for giving me the opportunity to review this manuscript.
Limsrivilai et al have reported the diagnostic yield of various endoscopic modalities in Thailand.
They proposed OGDs should not be done routinely for chronic diarrhea in their locality,
attempted to identify predictors of positive endoscopic yield, and recommended an investigative
algorithm.
Overall most of the manuscript is clear and concisely written. Clearly, it has the potential
to provide valuable insight into endoscopy practice within the region. However, there are
areas where the conclusions are not justified by the results or existing literature, and
further clarifications are needed. A major revision is recommended before the article can be
reconsidered for publication. My comments can be found below.
I wish the authors all the best for their revision and future submissions.
TITLE
Recommend changing this to "diagnostic yield" instead of "diagnostic performance". Diagnostic
performance implies the assessment of the usual epidemiological indices: sensitivity, specificity,
PPV, NPV, +LR, -LR, AUROC, and accuracy.
ABSTRACT
"Gastrointestinal endoscopy is recommended to investigate chronic diarrhea in Western
countries" - This is only true if certain conditions are met. Please see Ong et al, PMID: 31023694 ,
Figure 1. It is more accurate to say gastrointestinal endoscopy is frequently recommended for
the investigation of chronic diarrhea in Western countries.
" in Thai chronic diarrhea" - should read Thai patients with chronic diarrhea.
"were 11.6 g/dL and 3.8 g/dL" - I am not sure why albumin is reported unless protein-losing
enteropathy or malnutrition is common in Thailand? Albumin is mainly used to assess the
severity of IBD in the West. If these are not, I would remove the albumin level and add the
normal range in brackets for Hb in Thailand.
"in contrast to western" - should read "in contrast to Western countries"
" EGD did not add benefit to colonoscopy" - This cannot be made as a general statement because
it depends on what the suspected pathology is. For example, colonoscopy does not offer an added
benefit to OGD if Coeliac disease is suspected as the cause of chronic diarrhea. In this case, the
patient who had lymphoma was spared a colonoscopy because his OGD provided the diagnosis.
Introduction
"Diarrhea is defined by abnormal stool weight (>200 g/day) or frequency (>3 times/day)." Please
note not all clinicians use this definition as a gold standard. In the UK, the Bristol Stool chart,
frequency, and duration (for chronic diarrhea) are more important in clinical practice. Please see
the citation above. This definition also contradicts the authors' own definition of diarrhea which
includes ">1 occurrence of mucous-bloody stool per day for more than four weeks." Suggest
deleting the definition or discuss various versions of the definition. The former is easier.
"According to the American Society for Gastrointestinal Endoscopy guidelines, a diagnostic
colonoscopy should be performed to evaluate chronic diarrhea" - I cannot find this
recommendation in the reference provided. It says colonoscopy is "valuable" and should be
performed under certain circumstances. It does not say that it should be performed in all instances
to evaluate chronic diarrhea.
" Although gastrointestinal endoscopy is recommended" - As above, please add the word
"frequently" for correctness.
" Southeast Asia has a higher prevalence of gastrointestinal infections but a lower prevalence of
celiac and IBD" - Please provide some numbers and citations to justify this statement.
METHODS
There should be a separate subheading for Ethics
Please specify if biopsies obtained by endoscopy were included in the diagnostic process
and calculation of the yield. After all, endoscopy involves both macroscopic and microscopic
evaluation. In Western countries, biopsies are almost always taken on endoscopy when the
indication is chronic diarrhea. Were lower GI biopsies taken in every case? If so, please also
report the diagnostic yield of biopsies and if this differed from other methods of diagnosis
e.g. patients may have a normal biopsy but positive serological markers for an intestinal
neuroendocrine tumor which could be the cause of chronic diarrhea.
How was data normality assessed?
"We assessed the diagnostic yield of each endoscopic modality." In the statistical section, this
sentence does not contribute any new information. Please state how the diagnostic yield was
calculated or defined. Also, it is confusing to the reader because diagnostic yield and diagnostic
performance are used interchangeably. Please use "diagnostic yield" throughout the manuscript.
"Comparison of the diagnostic performance of EGD to colonoscopy, and colonoscopy to
colonoscopy without ileal intubation was performed using McNemar's test." McNemar's test
requires pairing. At the individual level, I can understand if the authors are comparing EGD yield
to colonoscopy yield in the same patient. However, in the latter, are the authors comparing a
patient who had a colonoscopy twice; one with and one without caecal intubation? Please clarify.
"Analysis to identify independent predictors of small bowel mucosal diseases in patients
with negative EGD and colonoscopy who underwent small bowel endoscopy was performed
based on logistic regression." Please provide as supplement data what variables went into the
regression model and how each variable was coded i.e. which ones were coded as categorical
and continuous.
" A p-value <0.05 was considered statistically significant." Please also specify if it is single-
tailed or two-tailed p values for all calculations.
Methods for univariate analyses have not been explained.
RESULT
"The mean hemoglobin and albumin levels were 11.54 g/dL and 3.76 g/dL, respectively." -
Please provide normal ranges for the Thai population.
Figure 1 needs editing. "EGD" and "colonoscopy" on the positive finding arm is reported the
breakdown of positive results of the procedures and not a diagnostic process. It does not flow
from the box above. Also for clarity, consider the labels EGD+ AND colonoscopy+ = 7, EGD-
AND colonoscopy+ = 43
Table 3 - Please explain how Odd's ratio were derived from continuous variables? It seems
illogical to build a single variable LR (logistic regression) model when a multiple LR is also
undertaken. Usually, univariate analyses use comparisons of different methods and parameters
e.g. mean or proportions to determine if actual differences in subgroups exist e.g. bloody
diarrhoea vs. no bloody diarrhoea or low albumin vs. normal albumin. It makes no sense in
trying to fit a LR curve of a variable that has no association on direct testing. Important variables
identified through univariate analyses can then be fitted into a multiple LR model so independent
predicts can be identified and p values "adjusted". The final multiple LR would also be more
accurate.
DISCUSSION
" In this study, we found the etiologies of chronic diarrhea in Thai patients to be different from
those in Western patients, particularly in small bowel diseases." It would be more insightful to
add some numbers side by side e.g. (X% vs.Y% to Z%).
" Furthermore, our study showed that the terminal ileum should be accessed because the
diagnostic yield would have been decreased from 42.7% to 39.4% if the terminal ileum had
not been intubated." TI intubation depends on clinical indication e.g. it would be pointless
if pseudomembranous colitis was observed on colonoscopy. It would be better to suggest TI
intubation if no lesions were found whilst ascending to the TI. Also, is this drop statistically
significant or negligible?
ASGE can be abbreviated in the introduction so the acronym can be used in the discussion.
"American Society for Gastrointestinal Endoscopy guideline recommends EGD for chronic
diarrhea work-up due to its potential for diagnosing celiac disease" This is not accurate. ASGE
recommends EGD only in the absence of significant findings on laboratory studies and lower
endoscopy." (Page 888). EGD is not done as a first-line procedure. In the UK, if coeliac serology
is negative and IgA levels are normal, an OGD is not routinely needed to screen for Coeliac
disease. If serology is positive, OGDs are usually done for tissue diagnosis.
" Interestingly, the involved small bowel segments causing chronic diarrhea in our cohort were at
more distal segments that are unreachable by EGD". It is more useful to include some indication
of location and frequency, e.g. D3-D4 X% jejunum Y%, ileum Z%.
"For the predictive factors associated with the diagnosis of small bowel mucosal diseases among
patients with negative EGD and colonoscopy, lower albumin level was the significant predictor
in univariate analysis, and it was almost significant in multivariate analysis. This result is in
accordant with the study by Song et al., which showed that hypoalbuminemia and hematochezia
were significant predictive factors for a positive diagnostic yield of VCE in patients with chronic
diarrhea.[7]" The paragraph needs to be re-written after clarification of the comments mentioned
under the results section. "Low" is not clearly defined, neither is a convincing relationship to
chronic diarrhea in this dataset at present. OR 0.50 suggests it is less likely. Do the authors mean
OR was 2?
Figure 3 - I have strong concerns with Figure 3. From Table 1, UC seems to be the most common
single etiology for chronic diarrhea (17.2%). If a Thai patient with severe undiagnosed UC
and hypoalbuminemia presented to a hospital in the region with chronic diarrhea, and a doctor
followed the algorithm, the outcome would be catastrophic. Hypoalbuminaemia is a feature
of severe UC and not just protein-losing enteropathy. Further, there are no reliable serological
or stool tests to diagnose IBD in the pre-endoscopy workup to pre-alert endoscopists, and
proceeding with a full colonoscopy with push enteroscopy in this situation runs a high risk of
perforation and death. It should be avoided at all costs in this instance until the patient recovers
from the episode. Figure 3 needs to be improved significantly or deleted.
Another limitation is that the study numbers are small and may not be representative of the wider
population e.g. some subgroups have less than 5 patients.
CONCLUSION
The conclusion will obviously have to be re-written once the authors consider all the points
above.