Title: Analysis of clinical features and prognostic factors in patients with Hepatic Hydrothorax:
A single-center study from China
Version: 3 Date: 28 May 2022
Reviewer's report:
Thanks for the authors for re-analyzing the data with the correct methods and for addressing
most of the points highlighted in the previous revision. This revised version of the paper helped
me to understand what the authors were considering as confounders in the previous version.
Although this revised version of the manuscript is clearly improved, it still has minor issues that
can be easily addressed. My main concerns are the analysis of factors associated with survival/
mortality and the interpretation the authors are giving to their findings.
The authors believe that performing univariate analyses allows them to identify confounders.
That is, the authors let the data decided what were the confounders. This is incorrect, a
confounder should be decided a priori, using scientific knowledge, and it is not determined by
a p-value. This is a common mistake in medical studies, but we must work in correcting them
to improve medical evidence.
The purpose of addressing confounding is to claim a causal relationship. By accepting that this is
an exploratory analysis, the authors don’t need to worry about confounding in their manuscript.
But also, they authors must avoid the use of a causal language in the interpretation of their
findings. The method they used only permits to detect predictors that are highly associated with
the outcome, after accounting for other predictors. Remember that association does not imply
causation.
In addition, when we talk about a variable as being a confounder, it implies that it confuses
the relationship between another two variables (a predictor of interest and an outcome). For
example, if you are interested in assessing the relationship between having ascites and survival,
gender might be a confounder if you believe that ascites is more common in males than females
(or the opposite) and you also believe that females live more than male (no p-value is required).
However, gender might not be a confounder for the relationship between having hyponatremia
and survival if you don’t believe that sodium levels are associated with gender (again, not
decided by a p-value). What would be the purpose of adjusting for gender if you are interested
in assessing the relationship between hyponatremia and survival? Moreover, there might be
other factors that are confounders for the relationship between gender and survival that were not
considered here (for example, comorbidities that are more common in females or males and that
are also associated with survival). In that case, a model that only controls for hyponatremia and
ascites in addition to gender might not be enough to remove confounding from the association
between gender and survival. Therefore, when we talk about confounders, we should refer with
respect to what relationship, not in general.
Finally, when assessing multiple factors, there exists the problem of multiple testing, you could
be getting some significant p-values only by random.  Also, models that control for many
variables could overfit the data. Therefore, I encourage the authors to state they are performing an
exploratory analysis and to include the corresponding limitation in the discussion (see comments
in detail below).
This is the detailed list of issues that need to be addressed:
I. Title
I strongly recommend modifying the title. I would change “Analysis of clinical features and
prognostic factors associated with Hepatic Hydrothorax” for “Analysis of clinical features and
prognostic factors in patients with Hepatic Hydrothorax”. This study did not identify factors
associated with Hepatic Hydrothorax. The analysis was performed in subjects with HH.
II. Abstract
1. Results section. It says “the estimated survival time was 21 (18-25) months”, please indicate
that 18-25 refers to the 95% confidence interval.
2. Results section. It says “After adjusting for potential confounders using a multivariable Cox
regression model…”. I suggest changing the wording to: “After controlling for covariates that
were associated with liver-related mortality in the univariate analysis…” because that is what
the authors did to select the variables that are called confounders. Alternatively, the authors may
just state, “In the multivariate analysis…”
3. In both results and conclusion sections, please remove the word “independently” in the
sentences saying “independently associated”. This term is commonly used to describe the
situation that a predictor is significant while "controlling for" the other predictors in the model. It
is better to described what was done and avoid using terminology that might convey an incorrect
message.
III. Methods/Statistical analysis section
1. This text is confusing: “Hypothesis testing was performed separately for continuous variables
in the Cox proportional risk model using the trend test with Schoenfeld residuals and for
categorical variables using the graphical method with cumulative risk functions”. It seems that
the authors are referring for testing the proportional hazard assumption, in that case, they could
just state “The proportional hazard assumption was assessed using the Schoenfeld residuals for
continuous variables and using the graphical method for categorical variables”.
2. It says “The variables that met the hypothesis test were incorporated into the univariate Cox
proportional risk model to assess the effect of different variables on survival time.”, does it
mean that variables that did not satisfy the proportional hazard assumption were not assessed
as associated with survival time? There are survival analysis methods to assess variables that
does not satisfy the proportional hazard assumption, although they are advanced methods. It is
fine to restrict your analysis to just this subset of the variables. However, you must be aware
that you are ignoring variables that might be associated with your outcome of interest and some
associations you found might be driven by those ignored variables.
3. I strongly recommend the authors to state that their analysis for identifying factors associated
with mortality/survival is an exploratory analysis.
4. In the text “After adjusting for other confounders, multivariate Cox regression models were
used to determine the correlation between statistically significant factors and the prognostic
impact of HH”. Again, I suggest changing the wording to: “After controlling for covariates that
were associated with liver-related mortality in the univariate analysis…”. Also, please change
the word “correlation” for “association”. Authors are referring to association here. There might
be the case that two variables are associated but uncorrelated (that is, with zero correlation).
5. Regarding the sentence “Survival outcomes were compared between groups using the
Kaplan–Meier method of log-rank tests”, I would like to note that the Cox regression models
also compare survival outcomes. Is the outcome here different to the one assessed in the previous
Cox regression models? Please clarify. Perhaps the authors should state that for categorical
variables, the survival outcomes were compared with both methods, and they used the Kaplan-
Meier estimates to display survival curves.
IV. Results
1. In section 3.4, it says “For overall survival without transplantation, the estimated follow-up
time was 18 (16.8-21.5) months, the estimated survival time was 21 (18-25) months”. What are
the numbers 16.8 – 21.5? the interquartile range? Please clarify. Also clarify what the numbers
18 – 25 mean.
2. In section 3.5, the text “In the multivariate Cox regression model, the possible confounders
considered were liver failure, hyponatremia, TBIL, and PT, and these four variables were further
removed to see the change in HR value of the target variable (male) after the removal of a
variable. If the change in HR value after removal was more than 10%, the variable was ultimately
retained. If not, the variable was removed” corresponds to the statistical analysis section in the
methods. Also, please change the word “confounder” for another word, for example, predictors
or variables.
3. In section 3.5, also change the word “confounders” in the sentence “After adjusting for
potential confounders using a multivariable Cox regression model…”.
4. In section 3.5, please remove the word “independently” in the sentence “…were found to be
independently associated with an increase in liver-related mortality (see Table 4)”.
5. In the last paragraph of section 3.5, please clarify what the numbers between parentheses
mean.
6. I did not see the “Etiology” variable in Table 4, don’t the authors believe that the cirrhosis
etiology may be associated with survival? Also, I believe that some comorbidities as diabetes,
hypertension, dyslipidemia, and cardiovascular disease might be associated with survival and
were not considered, why? Is It because the authors don’t believe those comorbidities might
be associated with survival? Or because they don’t have this data? Please state that in the
manuscript.
V. Discussion
1. In the first paragraph says “…and risk factors affecting prognostic survival were further
analyzed based on follow-up survival time.” Please change “risk factors affecting prognostic
survival” for “factors associated with survival”. Please avoid using a causal language.
2. In the seventh paragraph, the authors state “We also demonstrated that male sex and hepatic
encephalopathy were independently associated with an increase in liver-related mortality…”.
Please avoid using causal language. Remember that this was an exploratory analysis not a
confirmatory one. I recommend changing “demonstrated” by “found” and removing the word
“independently”.
3. In the paragraph of limitations, the third limitation is not accurate. The performed analysis
does not address confounding, confounding with respect to what relationship? I suggest
changing this limitation for “the analysis performed to identify potential risk factors is merely
exploratory and our findings are subject to random high bias”.
4. In the last paragraph, please remove the word “independent”.
VI. Authors' contributions
1. Please specify who analyzed the data.
Title: Analysis of clinical features and prognostic factors in patients with Hepatic Hydrothorax:
A single-center study from China
Version: 3 Date: 28 May 2022
Reviewer's report:
Thanks for the authors for re-analyzing the data with the correct methods and for addressing
most of the points highlighted in the previous revision. This revised version of the paper helped
me to understand what the authors were considering as confounders in the previous version.
Although this revised version of the manuscript is clearly improved, it still has minor issues that
can be easily addressed. My main concerns are the analysis of factors associated with survival/
mortality and the interpretation the authors are giving to their findings.
The authors believe that performing univariate analyses allows them to identify confounders.
That is, the authors let the data decided what were the confounders. This is incorrect, a
confounder should be decided a priori, using scientific knowledge, and it is not determined by
a p-value. This is a common mistake in medical studies, but we must work in correcting them
to improve medical evidence.
The purpose of addressing confounding is to claim a causal relationship. By accepting that this is
an exploratory analysis, the authors don’t need to worry about confounding in their manuscript.
But also, they authors must avoid the use of a causal language in the interpretation of their
findings. The method they used only permits to detect predictors that are highly associated with
the outcome, after accounting for other predictors. Remember that association does not imply
causation.
In addition, when we talk about a variable as being a confounder, it implies that it confuses
the relationship between another two variables (a predictor of interest and an outcome). For
example, if you are interested in assessing the relationship between having ascites and survival,
gender might be a confounder if you believe that ascites is more common in males than females
(or the opposite) and you also believe that females live more than male (no p-value is required).
However, gender might not be a confounder for the relationship between having hyponatremia
and survival if you don’t believe that sodium levels are associated with gender (again, not
decided by a p-value). What would be the purpose of adjusting for gender if you are interested
in assessing the relationship between hyponatremia and survival? Moreover, there might be
other factors that are confounders for the relationship between gender and survival that were not
considered here (for example, comorbidities that are more common in females or males and that
are also associated with survival). In that case, a model that only controls for hyponatremia and
ascites in addition to gender might not be enough to remove confounding from the association
between gender and survival. Therefore, when we talk about confounders, we should refer with
respect to what relationship, not in general.
Finally, when assessing multiple factors, there exists the problem of multiple testing, you could
be getting some significant p-values only by random.  Also, models that control for many
variables could overfit the data. Therefore, I encourage the authors to state they are performing an
exploratory analysis and to include the corresponding limitation in the discussion (see comments
in detail below).
This is the detailed list of issues that need to be addressed:
I. Title
I strongly recommend modifying the title. I would change “Analysis of clinical features and
prognostic factors associated with Hepatic Hydrothorax” for “Analysis of clinical features and
prognostic factors in patients with Hepatic Hydrothorax”. This study did not identify factors
associated with Hepatic Hydrothorax. The analysis was performed in subjects with HH.
II. Abstract
1. Results section. It says “the estimated survival time was 21 (18-25) months”, please indicate
that 18-25 refers to the 95% confidence interval.
2. Results section. It says “After adjusting for potential confounders using a multivariable Cox
regression model…”. I suggest changing the wording to: “After controlling for covariates that
were associated with liver-related mortality in the univariate analysis…” because that is what
the authors did to select the variables that are called confounders. Alternatively, the authors may
just state, “In the multivariate analysis…”
3. In both results and conclusion sections, please remove the word “independently” in the
sentences saying “independently associated”. This term is commonly used to describe the
situation that a predictor is significant while "controlling for" the other predictors in the model. It
is better to described what was done and avoid using terminology that might convey an incorrect
message.
III. Methods/Statistical analysis section
1. This text is confusing: “Hypothesis testing was performed separately for continuous variables
in the Cox proportional risk model using the trend test with Schoenfeld residuals and for
categorical variables using the graphical method with cumulative risk functions”. It seems that
the authors are referring for testing the proportional hazard assumption, in that case, they could
just state “The proportional hazard assumption was assessed using the Schoenfeld residuals for
continuous variables and using the graphical method for categorical variables”.
2. It says “The variables that met the hypothesis test were incorporated into the univariate Cox
proportional risk model to assess the effect of different variables on survival time.”, does it
mean that variables that did not satisfy the proportional hazard assumption were not assessed
as associated with survival time? There are survival analysis methods to assess variables that
does not satisfy the proportional hazard assumption, although they are advanced methods. It is
fine to restrict your analysis to just this subset of the variables. However, you must be aware
that you are ignoring variables that might be associated with your outcome of interest and some
associations you found might be driven by those ignored variables.
3. I strongly recommend the authors to state that their analysis for identifying factors associated
with mortality/survival is an exploratory analysis.
4. In the text “After adjusting for other confounders, multivariate Cox regression models were
used to determine the correlation between statistically significant factors and the prognostic
impact of HH”. Again, I suggest changing the wording to: “After controlling for covariates that
were associated with liver-related mortality in the univariate analysis…”. Also, please change
the word “correlation” for “association”. Authors are referring to association here. There might
be the case that two variables are associated but uncorrelated (that is, with zero correlation).
5. Regarding the sentence “Survival outcomes were compared between groups using the
Kaplan–Meier method of log-rank tests”, I would like to note that the Cox regression models
also compare survival outcomes. Is the outcome here different to the one assessed in the previous
Cox regression models? Please clarify. Perhaps the authors should state that for categorical
variables, the survival outcomes were compared with both methods, and they used the Kaplan-
Meier estimates to display survival curves.
IV. Results
1. In section 3.4, it says “For overall survival without transplantation, the estimated follow-up
time was 18 (16.8-21.5) months, the estimated survival time was 21 (18-25) months”. What are
the numbers 16.8 – 21.5? the interquartile range? Please clarify. Also clarify what the numbers
18 – 25 mean.
2. In section 3.5, the text “In the multivariate Cox regression model, the possible confounders
considered were liver failure, hyponatremia, TBIL, and PT, and these four variables were further
removed to see the change in HR value of the target variable (male) after the removal of a
variable. If the change in HR value after removal was more than 10%, the variable was ultimately
retained. If not, the variable was removed” corresponds to the statistical analysis section in the
methods. Also, please change the word “confounder” for another word, for example, predictors
or variables.
3. In section 3.5, also change the word “confounders” in the sentence “After adjusting for
potential confounders using a multivariable Cox regression model…”.
4. In section 3.5, please remove the word “independently” in the sentence “…were found to be
independently associated with an increase in liver-related mortality (see Table 4)”.
5. In the last paragraph of section 3.5, please clarify what the numbers between parentheses
mean.
6. I did not see the “Etiology” variable in Table 4, don’t the authors believe that the cirrhosis
etiology may be associated with survival? Also, I believe that some comorbidities as diabetes,
hypertension, dyslipidemia, and cardiovascular disease might be associated with survival and
were not considered, why? Is It because the authors don’t believe those comorbidities might
be associated with survival? Or because they don’t have this data? Please state that in the
manuscript.
V. Discussion
1. In the first paragraph says “…and risk factors affecting prognostic survival were further
analyzed based on follow-up survival time.” Please change “risk factors affecting prognostic
survival” for “factors associated with survival”. Please avoid using a causal language.
2. In the seventh paragraph, the authors state “We also demonstrated that male sex and hepatic
encephalopathy were independently associated with an increase in liver-related mortality…”.
Please avoid using causal language. Remember that this was an exploratory analysis not a
confirmatory one. I recommend changing “demonstrated” by “found” and removing the word
“independently”.
3. In the paragraph of limitations, the third limitation is not accurate. The performed analysis
does not address confounding, confounding with respect to what relationship? I suggest
changing this limitation for “the analysis performed to identify potential risk factors is merely
exploratory and our findings are subject to random high bias”.
4. In the last paragraph, please remove the word “independent”.
VI. Authors' contributions
1. Please specify who analyzed the data.
Please review this paper.
user
Title: Analysis of clinical features and prognostic factors in patients with Hepatic Hydrothorax:
A single-center study from China
Version: 3 Date: 28 May 2022
Reviewer's report:
Thanks for the authors for re-analyzing the data with the correct methods and for addressing
most of the points highlighted in the previous revision. This revised version of the paper helped
me to understand what the authors were considering as confounders in the previous version.
Although this revised version of the manuscript is clearly improved, it still has minor issues that
can be easily addressed. My main concerns are the analysis of factors associated with survival/
mortality and the interpretation the authors are giving to their findings.
The authors believe that performing univariate analyses allows them to identify confounders.
That is, the authors let the data decided what were the confounders. This is incorrect, a
confounder should be decided a priori, using scientific knowledge, and it is not determined by
a p-value. This is a common mistake in medical studies, but we must work in correcting them
to improve medical evidence.
The purpose of addressing confounding is to claim a causal relationship. By accepting that this is
an exploratory analysis, the authors don’t need to worry about confounding in their manuscript.
But also, they authors must avoid the use of a causal language in the interpretation of their
findings. The method they used only permits to detect predictors that are highly associated with
the outcome, after accounting for other predictors. Remember that association does not imply
causation.
In addition, when we talk about a variable as being a confounder, it implies that it confuses
the relationship between another two variables (a predictor of interest and an outcome). For
example, if you are interested in assessing the relationship between having ascites and survival,
gender might be a confounder if you believe that ascites is more common in males than females
(or the opposite) and you also believe that females live more than male (no p-value is required).
However, gender might not be a confounder for the relationship between having hyponatremia
and survival if you don’t believe that sodium levels are associated with gender (again, not
decided by a p-value). What would be the purpose of adjusting for gender if you are interested
in assessing the relationship between hyponatremia and survival? Moreover, there might be
other factors that are confounders for the relationship between gender and survival that were not
considered here (for example, comorbidities that are more common in females or males and that
are also associated with survival). In that case, a model that only controls for hyponatremia and
ascites in addition to gender might not be enough to remove confounding from the association
between gender and survival. Therefore, when we talk about confounders, we should refer with
respect to what relationship, not in general.
Finally, when assessing multiple factors, there exists the problem of multiple testing, you could
be getting some significant p-values only by random.  Also, models that control for many
variables could overfit the data. Therefore, I encourage the authors to state they are performing an
exploratory analysis and to include the corresponding limitation in the discussion (see comments
in detail below).
This is the detailed list of issues that need to be addressed:
I. Title
I strongly recommend modifying the title. I would change “Analysis of clinical features and
prognostic factors associated with Hepatic Hydrothorax” for “Analysis of clinical features and
prognostic factors in patients with Hepatic Hydrothorax”. This study did not identify factors
associated with Hepatic Hydrothorax. The analysis was performed in subjects with HH.
II. Abstract
1. Results section. It says “the estimated survival time was 21 (18-25) months”, please indicate
that 18-25 refers to the 95% confidence interval.
2. Results section. It says “After adjusting for potential confounders using a multivariable Cox
regression model…”. I suggest changing the wording to: “After controlling for covariates that
were associated with liver-related mortality in the univariate analysis…” because that is what
the authors did to select the variables that are called confounders. Alternatively, the authors may
just state, “In the multivariate analysis…”
3. In both results and conclusion sections, please remove the word “independently” in the
sentences saying “independently associated”. This term is commonly used to describe the
situation that a predictor is significant while "controlling for" the other predictors in the model. It
is better to described what was done and avoid using terminology that might convey an incorrect
message.
III. Methods/Statistical analysis section
1. This text is confusing: “Hypothesis testing was performed separately for continuous variables
in the Cox proportional risk model using the trend test with Schoenfeld residuals and for
categorical variables using the graphical method with cumulative risk functions”. It seems that
the authors are referring for testing the proportional hazard assumption, in that case, they could
just state “The proportional hazard assumption was assessed using the Schoenfeld residuals for
continuous variables and using the graphical method for categorical variables”.
2. It says “The variables that met the hypothesis test were incorporated into the univariate Cox
proportional risk model to assess the effect of different variables on survival time.”, does it
mean that variables that did not satisfy the proportional hazard assumption were not assessed
as associated with survival time? There are survival analysis methods to assess variables that
does not satisfy the proportional hazard assumption, although they are advanced methods. It is
fine to restrict your analysis to just this subset of the variables. However, you must be aware
that you are ignoring variables that might be associated with your outcome of interest and some
associations you found might be driven by those ignored variables.
3. I strongly recommend the authors to state that their analysis for identifying factors associated
with mortality/survival is an exploratory analysis.
4. In the text “After adjusting for other confounders, multivariate Cox regression models were
used to determine the correlation between statistically significant factors and the prognostic
impact of HH”. Again, I suggest changing the wording to: “After controlling for covariates that
were associated with liver-related mortality in the univariate analysis…”. Also, please change
the word “correlation” for “association”. Authors are referring to association here. There might
be the case that two variables are associated but uncorrelated (that is, with zero correlation).
5. Regarding the sentence “Survival outcomes were compared between groups using the
Kaplan–Meier method of log-rank tests”, I would like to note that the Cox regression models
also compare survival outcomes. Is the outcome here different to the one assessed in the previous
Cox regression models? Please clarify. Perhaps the authors should state that for categorical
variables, the survival outcomes were compared with both methods, and they used the Kaplan-
Meier estimates to display survival curves.
IV. Results
1. In section 3.4, it says “For overall survival without transplantation, the estimated follow-up
time was 18 (16.8-21.5) months, the estimated survival time was 21 (18-25) months”. What are
the numbers 16.8 – 21.5? the interquartile range? Please clarify. Also clarify what the numbers
18 – 25 mean.
2. In section 3.5, the text “In the multivariate Cox regression model, the possible confounders
considered were liver failure, hyponatremia, TBIL, and PT, and these four variables were further
removed to see the change in HR value of the target variable (male) after the removal of a
variable. If the change in HR value after removal was more than 10%, the variable was ultimately
retained. If not, the variable was removed” corresponds to the statistical analysis section in the
methods. Also, please change the word “confounder” for another word, for example, predictors
or variables.
3. In section 3.5, also change the word “confounders” in the sentence “After adjusting for
potential confounders using a multivariable Cox regression model…”.
4. In section 3.5, please remove the word “independently” in the sentence “…were found to be
independently associated with an increase in liver-related mortality (see Table 4)”.
5. In the last paragraph of section 3.5, please clarify what the numbers between parentheses
mean.
6. I did not see the “Etiology” variable in Table 4, don’t the authors believe that the cirrhosis
etiology may be associated with survival? Also, I believe that some comorbidities as diabetes,
hypertension, dyslipidemia, and cardiovascular disease might be associated with survival and
were not considered, why? Is It because the authors don’t believe those comorbidities might
be associated with survival? Or because they don’t have this data? Please state that in the
manuscript.
V. Discussion
1. In the first paragraph says “…and risk factors affecting prognostic survival were further
analyzed based on follow-up survival time.” Please change “risk factors affecting prognostic
survival” for “factors associated with survival”. Please avoid using a causal language.
2. In the seventh paragraph, the authors state “We also demonstrated that male sex and hepatic
encephalopathy were independently associated with an increase in liver-related mortality…”.
Please avoid using causal language. Remember that this was an exploratory analysis not a
confirmatory one. I recommend changing “demonstrated” by “found” and removing the word
“independently”.
3. In the paragraph of limitations, the third limitation is not accurate. The performed analysis
does not address confounding, confounding with respect to what relationship? I suggest
changing this limitation for “the analysis performed to identify potential risk factors is merely
exploratory and our findings are subject to random high bias”.
4. In the last paragraph, please remove the word “independent”.
VI. Authors' contributions
1. Please specify who analyzed the data.
assistant