Review for 10.1186/s12876-019-1123-9 (2019)

Reviewer ’s report  
 
Title: The Magnitude and correlates of Esophageal Varices among newly diagnosed Cirrhotic 
Patients Undergoing Screening Upper Gastrointestinal Endosc ope bef ore incident bleeding in 
North -Western Tanzania; a Cross Sectional  Study  
 
Version: 1 Date: 25 Jun 2019  
 
Reviewer: Research Square  
 
Reviewer's report:  
 
"STATISTICAL REVIEWER ASSESSMENT:  
 
Is the study design appropriate for the research question (considering whether the analyzed 
population accurately reflects the design and whether you see any p roblems with 
control/comparison groups, e.g., likely confounders)?  
 
No - there are major issues  
 
 
Are methodologies adequate and well implemented (considering whether assumptions are 
addressed and whether analyses are robust)?  
 
No - there are major issues  
 
 
Are the analyses adequately communicated (considering whether reporting details are adequate 
and whether figures and tables are well labeled and described)?  
 
No - there are major issues  
 
 
Does the interpretation accurately reflect the analyses without overstat ement (considering 
whether limitations/bias are acknowledged and whether accurate descriptors, e.g., 'significant', 
are used?  
 
No - there are major issues  
 
 
Could an appropriately REVISED version of this work represent a statistically sound 
contribution?  
 
Maybe - with major revisions  
 
 
STATISTICAL REVIEWER COMMENTS:  
 
This study sought to estimate the prevalence of and factors associated with presence of 
esophageal varices based on a cross sectional sample of 223 adult patients who were newly 
diagnosed with liver cirrhosis at a medical center in Tanzania. The authors al so attempted to 
assess the diagnostic accuracy of some non -invasive parameters in identifying the presence of 
varices in cirrhotic patients as opposed to standard endoscopic assessment.  
 
The cross sectional design of the study allows for an estimation of the prevalence of esophageal 
varices in patients with liver cirrhosis but as the authors acknowledge, generalizability is limited 
in a single center study. In terms of the suitability of the study design, I am mostly concerned 
with the inadequacy of the cr oss-sectional data collection in assessing associations and 
diagnostic/predictive ability of recorded variables. This is because the timing of events was not 
examined (e.g., which occurred first, thrombocytopenia or esophageal varices?). Moreover, it 
seems  that the choice of variables for inclusion was exploratory and the rationale behind 
assessing each variable as a risk factor or predictor for esophageal varices is difficult to 
understand.   
 
Regarding statistical analysis, the model building process in l ogistic regression is poorly 
explained and/or reported (Multicolinearity? Variable selection based solely on univariate p -
values? Handling of numerical/continuous variables? Linearity in the logit? Effect modifiers? 
Goodness -of-fit?). Despite that the auth ors seem to understand the need for a multivariable 
analysis in assessing associations, they seem to ignore this when assessing predictive ability. The 
latter seems to have been done selectively and only in a univariate manner, which is difficult to 
make s ense. Moreover, there are obvious errors in the reporting of the diagnostic accuracy 
measures (e.g. specificity was wrongly calculated).  
 
Presentation of data and results requires substantial improvements and I have noted some issues 
of interpretation tha t require attention (see specific comments below). I would have liked to see 
some more consistency with the STROBE reporting guidelines for observational studies.  The 
manuscript requires substantial editing for English language.  
 
Please see below for spe cific comments.  
 
 
REQUESTED REVISIONS:  
 
Specific comments:  
 
On study design:  
 
(1) (materials and methods, 1st paragraph). A standard precision -based sample size 
calculation for prevalence proportions is reported here. The calculation was based on an 
antici pated prevalence of esophageal varices of 26% as seen in previous studies. The 
authors report a required sample size of n=205. I could not confirm this calculation. 
Using a standard confidence level of 95% and a margin of error of 5%, I calculated that a 
substantially larger sample size of n = 296 is required. The authors should clearly state 
how they calculated the required sample, including the confidence level and the margin 
of error (absolute level of precision) used.  
 
(2) (materials and methods). You s hould clearly define all predictors assessed in your study 
(and included in tables 1, 2 and 3), including variables that were included as potential 
confounders and effect modifiers. You should clearly state what is the rationale for 
including each variable  (prior studies, clinical knowledge, exploratory analysis?).  
 
(3) (materials and methods). Many predictor variables, such as thrombocytopenia, ascites, 
hepatorenal syndrome etc, are complications of liver cirrhosis and so is esophageal 
varices which was stu dies as the outcome variable. For association and prediction to 
make sense, exposures should precede the outcome. How did the authors ensure that 
factors recorded as potential predictors preceded the occurrence of esophageal varices?  
 
(4) (materials and met hods). An explanation of how numerical (quantitative continuous) 
variables were handled in the analyses is missing. It appears from your results that 
arbitrary cut -offs were used to categorize continuous variables (e.g. age &gt;60 yrs, 
PLT&gt;100 10^3µL, S pleen size &gt;14cm, ΗΒ &lt;10g/dL, PSDR &lt;909, 
ALB &lt;3.5g/dL). Such grouping choices may have important consequences for the 
analysis. From a statistical point of view groupings lose information, reduce statistical 
power (especially when dichotomization is used) and residual confounding may occur 
when grouping continuous confounders (such as age) [see STROBE elaboration and 
explanation for more details on these issues]. Therefore, the authors should state and 
explain the rationale for dichotomizing contin uous predictors and the choices in cut -offs. 
Why didn't the authors retain the continuous nature of the variables? Nonlinearities can 
be easily handled in logistic regression by using e.g. restricted cubic splines.  
 
 
On data analysis:  
 
(5) (materials and meth ods). How was multicollinearity between assessed predictors ruled 
out in logistic regression?  
 
(6) (materials and methods). Was potential effect modifiers (interactions) assessed in logistic 
regression?  
 
(7) (materials and methods). The authors selected vari ables for multivariable logistic 
regression analysis based solely on low p -values (p &lt;0.05) on univariate analysis. The 
reasons behind this strategy are difficult to understand because a variable may not appear 
significant in univariate analysis due to c onfounding (i.e. its effect suppressed by other 
confounders); the approach taken by the authors would fail to adjust for such negative 
confounding. Usually much higher p -value cut -offs (e.g. p &lt;0.25) are used for variable 
selection, including considerati ons for changing beta coefficients. I strongly recommend 
that the authors consult and revise their analysis in accordance with guidelines for 
performing and reporting multivariable analyses (e.g. Am J Transplant 2010; 10: 1695 -
1703 or Chest 2007;131;628 -632). 
 
(8) (materials and methods). How was the final logistic regression model assessed? You 
should report goodness -of-fit tests (e.g. Hosmer -Lemeshow test). The area under ROC 
curve (c -index) should be provided given that prediction is of interest.  
 
(9) (materials and methods, and results, Table 3). What is the rational in choosing "non -
invasive predictors" for diagnostic accuracy evaluation? Why was this done in a 
univariate manner only? Why didn't the authors assess the predictive ability of the 
multivariab le model as a set of identified predictors? (see e.g. TRIPOD guidelines for 
relevant methods).  
 
(10) (results, table 2). Being married was identified as significantly and independently 
associated with an increased likelihood of having esophageal varices. Th is finding was 
vaguely commented by the authors, seems difficult to explain and raises concerns about 
residual confounding.  
 
(11) (results, Table 2). Why wasn't PSDR included in the analysis of Table 2?  
 
(12) (results). In relation to comment (8) above the univariate assessment of the predictive 
ability of the variables is difficult to understand. For example, the diagnostic accuracy of 
being married in predicting esophageal varices would be Sensitivity = 61.4% ,  
Specificity=69.6%, which is much better than using PLT &lt;100 ! Predictive values when 
using marital status to predict esophageal varices would be PPV=56.8% and NPV = 
73.4%, which are much better compared to most of the variables in Table 2! Does 
examin ing diagnostic accuracy in the way that the authors have done make sense?  
 
(13) (results, Table 3). How was specificity calculated? It appears that the authors have 
calculated the opposite of specificity. For example, among the 135 patients without 
varices  96 did not have a PLT &lt;100. The ability to detect patients without varices based 
on a negative PLT &lt;100 should be 96/135 = 71.1% and not 28.9% as reported. All 
specificity values should be checked and corrected.  
 
(14) (results, Table 3). My question r egarding the dichotomization of variables that are 
continuous in nature holds also for Table 3. Isn't it better to retain a continuous scale and 
assess predictive ability using the ROC curve area?  
 
 
On interpretation:  
 
(15) (conclusions) You conclude (in th e abstract and the main text) that your findings 
emphasize the imperative of routine endoscopic assessment for esophageal varices in 
cirrhotic patients. This is common knowledge that has been long incorporated in 
guidelines.  
 
(16) (discussion) Regarding th e association of esophageal varices risk to marital status, your 
discussion implies that this is confounded by the age and sex of the patients. Why did you 
not check this in logistic regression? Did you try to include gender into the model to see 
what happ ens with the effect of marital status? Did you try to include age as a continuous 
variable (rather than dichotomized)? Did you consider the potential for residual 
confounding?  
 
 
On presentation and reporting:  
 
(17) (table 3) What is the point of reporting th e univariate OR in Table 3?  
 
(18) Confidence intervals for all prevalence proportions of interest should be reported in text. 
For example, you state a point estimate of 39.5% for the prevalence of varices - you need 
to report a confidence interval for the readers to understand the degree of statistical 
precision in your estimate. The same holds true for all diagnostic accuracy percentages 
reported in table 3. In graphs (figures 1 and 2) you should present confidence intervals 
using error bars.  
 
(19) All per centages (in tables and text) should be rounded to one decimal (to avoid a false 
sense of exaggerated accuracy), e.g. replace 35.56% by 35.6%. Absolute numbers should 
not have a leasing zero (e.g. in Table 2, you should write 31 not 031).  
 
(20) (results/pre dictive values) The phrase "at 95%CI with a p -value of …" does not make 
sense.  
 
(21) The paper should be revised in accordance to the STROBE guidelines for observational 
studies (see e.g. Ann Intern Med. 2007;147:W -163-W-194). Guidelines for performing 
and reporting multivariable analyses should also be consulted (see e.g. Am J Transplant 
2010; 10: 1695 -1703 or Chest 2007;131;628 -632). Relevant checklists should be 
provided with the revision.  
 
(22) The manuscript requires substantial improvement for English language. I advise the 
authors to seek help from someone with full proficiency in English for scientific writing 
purposes. " 
 
Are the methods appropriate and well de scribed?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions dra wn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistica l review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration  of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1.  Have you in the past five years received reimbursements, f ees, funding, or salary 
from an organisation that may in any way gain or lose financial ly from the 
publication of this manuscript, either now or in the future?  
 
2.  Do you hold any stocks or shares in an organisation t hat may in any way gain or 
lose financially from the publication of this  manuscript, either now or in the 
future?  
 
3.  Do you hold or are you currently applying for any patents  relating to the content 
of the manuscript?  
 
4.  Have you received reimbursements, fees, funding, or salary from an organization 
that holds or has applied f or patents relating to the content of the manuscript?  
 
5.  Do you have any other financial competing interests?  
 
6.  Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
This reviewer has been recruited by a partner organization, Research Sq uare. Reviewers with 
declared or apparent competing interests are not utilized for these reviews. This reviewer has 
agreed to publication of their comments online under a Creative Commons Attribution License 
attributed to Research Square and was paid a sma ll honorarium for completing the review within 
a specified timeframe. Honoraria for reviews such as this are paid regardless of the reviewer 
recommendation.  
 
I agree to the open peer review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepte d for publication,  my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.or g/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal