Title: Analysis of clinical features and prognostic factors in patients with Hepatic Hydrothorax:
A single-center study from China
Version: 1 Date: 27 Apr 2022
Reviewer's report:
Thank you for the opportunity to review this manuscript. In this study, the authors describe the
characteristics at diagnosis and relevant outcomes during follow-up of a retrospective cohort of
131 individuals with cirrhosis and hepatic hydrothorax attended at a single hospital in China.
Although the topic is of high relevance due to the limited number of cohort studies on hepatic
hydrothorax, this study has major methodological issues than must be addressed to provide
good evidence. I strongly recommend the authors to consult a biostatistician with expertise in
survival analysis to perform the statistical analysis. I also recommend the authors to adhere to
the STROBE guidelines for cohort studies.
Major issues:
1. Abstract:
a. Being statistically significant in a multivariate Cox proportional hazard model does not imply
being an independent risk factor for death. Were confounders included in the model? Note:
being a confounder does not depend on a p-value from a univariate Cox regression; confounder
must be chosen a priori based on scientific knowledge. Also, I recommend avoiding the term
“risk factor” since these results come from an exploratory analysis (the authors performed many
hypothesis tests) and do not imply causality. Instead, they may word “factors associated with”.
b. When there are censored data, as is the case for survival here (30 individuals were alive at the
end of the study), the mean is not an appropriate measure of centrality for survival time.
2. Methods:
a. Outcomes section:
i. It is not clear the meaning of the sentence “Outcomes were death or and loss to follow-up as
endpoint events”. Since the authors performed a survival analysis, the outcome should be time
to death (a time to event type outcome). The time to death value for a patient who lost follow-
up is considered as right-censored.
b. Statistical analysis section:
i. Was the proportional hazard assumption assessed for each Cox regression model? Please
indicate how this assumption was assessed for univariate and multivariate models. The KM
survival curves suggests the assumption might not hold for some covariates. There are ways to
handle this, please consult a biostatistician.
ii. It is state that multivariate Cox regression models were adjusted for other confounders,
what other confounders? Please specify the confounders that were considered. Note: being a
confounder does not depend on a p-value from a univariate Cox regression; confounder must be
chosen a priori based on scientific knowledge.
3. Results:
a. Treatment and mortality section:
i. As previously noted, the use of mean for the survival time variable is not appropriate because
this variable is subject to right-censoring. Please consult with a biostatistician with expertise in
survival analysis.
ii. What do the authors mean by death and lost of follow-up endpoints in the sentence “A total
of 101 patients experienced death and lost to follow-up endpoints”? Please clarify.
b. Analysis of factors associated with the prognostic impact of HH
i. The validity of the hazard ratios provided here rely on the proportional hazard assumption.
ii. Again, authors are using mean to summarize survival times, this is incorrect. Individuals
that haven’t died by the end of follow-up also provided information about survival time; this
information should be considered as well.
4. Discussion
a. The authors stated that “After multifactorial analysis, the findings indicated that liver
encephalopathy, hyponatremia, and MELD score were independent risk factors for prognostic
survival in HH”. Again, please avoid the term “risk factor” since these results come from an
exploratory analysis.
5. Tables
a. Table 3. Again, survival time is summarized as mean and standard deviation, this is incorrect.
b. Table 4. What variables were considered as confounders? Please specify.
c. Table 4. Did authors include in the same multivariate model the variables Hepatic
encephalopathy, Hyponatremia, Child–Pugh Score, MELD Score and MELD-Na Score? if
that is the case, the interpretation of the parameters is very complicated. For example, the
interpretation of the HR for MELD score would be “among individuals of the same gender,
same liver failure status, same hepatic encephalopathy status, same hyponatremia status, same
TBIL (umol/L) value, same PT (s), same Child–Pugh Score, same MELD-Na Score and same
ALBI Score, the HR for death comparing individuals who differ in their MELD score by 1 unit
is 1.063 95% CI (1.009, 1.121). It would be very hard to have individuals with different MELD-
score but who are identical in the other covariates included in the multivariate model.
Minor issues:
1. Abstract
d. A Cox regression assumes proportional hazards not proportional risks. Hazard and risks are
not the same.
e. The numbers provided are not mortality rates, they are cumulative mortalities. Please provide
the p-value for comparing the survival curves between men and women.
2. Methods
a. Study population section:
i. At the end of this section, it is stated that “Written informed consent was obtained from all
participants”, was this a general informed consent that the hospital obtains from all attended
patients or a specific informed consent for this study (very improbable in a retrospective study)?
Please clarify if the informed consent was specific for this study or a general informed consent
obtained from all patients attended at the hospital (in which case is usually waived by the Ethics
Committee).
b. Statistical analysis section:
i. What do authors mean by parametric continuous variables? My guess is that for each
continuous variable, the authors performed a test to assess if the data might follow a normal
distribution, and the variable was assumed as normally distributed when they failed to reject
the null hypothesis. If this is the case, please state it clearly and indicate the test for normality
that was used. Note: there are many parametric distribution for continuous variables: normal,
exponential, log-normal, gamma, chi-squared, etc.
3. Results
a. In general, please provide all numbers with only 2 or 3 significant digits. This will improve
the reading.
b. Demographics section:
i. The authors stated that “The prevalence of HH was 2.3%”. This number is not a prevalence
because HH were not assessed at a unique point in time. This number is only the proportion of
patients with cirrhosis diagnosis who developed HH at some time during an irregular follow-
up. The authors might compute the cumulative incidence of HH at a given time after cirrhosis
diagnosis or the overall incidence rate of HH by incorporating the time from cirrhosis diagnosis
to development of HH. These number would be meaningful. The provided number (2.3%) does
not represent a meaningful quantity and depends on the time patients the 5698 patients with
decompensated cirrhosis were followed-up.
ii. The authors stated that “HH was more common in men than in women”. This implies that the
proportion of men that developed HH among all men with decompensated cirrhosis is higher that
the proportion of women that developed HH among all women with decompensated cirrhosis.
However, these numbers are not provided. Please provide those numbers. Note: if the authors
were referring to the fact that the male-to-female ratio was 1.67:1 among the 131 individuals
with HH, this only imply that there were more males than females among the individuals with
HH, but it does not give any information about how common HH was among men or women.
c. Treatment and mortality section:
i. There is no need to provide the cumulative mortality at 30 days, 60 days, 90 days, 6 months,
1 year, 2 years, 3 years, 4 years and 5 years for males and females. The authors might refer the
reader to Figure 2.
ii. The authors stated that “it is clear that the mortality rate for males is significantly higher than
that for females at all time periods”. Please provide the p-value obtained from comparing the
survival curves.
d. Analysis of factors associated with the prognostic impact of HH
i. Define HR and CI only once.
4. Tables
a. All tables. Please provide all numbers with only 2 or 3 significant digits. This will improve
the reading.
5. Figures
a. Figure 2. The y axis label corresponds to “survival” or “survival probability” but not
cumulative survival. The x axis corresponds to time after HH diagnosis not survival. At each
time after the HH diagnosis the figure shows the survival probability at that time.
b. Figure 2. Values of p = 0.000 must be changed to p < 0.001.
c. Figure 2. Please provide the risk table below each plot.
Title: Analysis of clinical features and prognostic factors in patients with Hepatic Hydrothorax:
A single-center study from China
Version: 1 Date: 27 Apr 2022
Reviewer's report:
Thank you for the opportunity to review this manuscript. In this study, the authors describe the
characteristics at diagnosis and relevant outcomes during follow-up of a retrospective cohort of
131 individuals with cirrhosis and hepatic hydrothorax attended at a single hospital in China.
Although the topic is of high relevance due to the limited number of cohort studies on hepatic
hydrothorax, this study has major methodological issues than must be addressed to provide
good evidence. I strongly recommend the authors to consult a biostatistician with expertise in
survival analysis to perform the statistical analysis. I also recommend the authors to adhere to
the STROBE guidelines for cohort studies.
Major issues:
1. Abstract:
a. Being statistically significant in a multivariate Cox proportional hazard model does not imply
being an independent risk factor for death. Were confounders included in the model? Note:
being a confounder does not depend on a p-value from a univariate Cox regression; confounder
must be chosen a priori based on scientific knowledge. Also, I recommend avoiding the term
“risk factor” since these results come from an exploratory analysis (the authors performed many
hypothesis tests) and do not imply causality. Instead, they may word “factors associated with”.
b. When there are censored data, as is the case for survival here (30 individuals were alive at the
end of the study), the mean is not an appropriate measure of centrality for survival time.
2. Methods:
a. Outcomes section:
i. It is not clear the meaning of the sentence “Outcomes were death or and loss to follow-up as
endpoint events”. Since the authors performed a survival analysis, the outcome should be time
to death (a time to event type outcome). The time to death value for a patient who lost follow-
up is considered as right-censored.
b. Statistical analysis section:
i. Was the proportional hazard assumption assessed for each Cox regression model? Please
indicate how this assumption was assessed for univariate and multivariate models. The KM
survival curves suggests the assumption might not hold for some covariates. There are ways to
handle this, please consult a biostatistician.
ii. It is state that multivariate Cox regression models were adjusted for other confounders,
what other confounders? Please specify the confounders that were considered. Note: being a
confounder does not depend on a p-value from a univariate Cox regression; confounder must be
chosen a priori based on scientific knowledge.
3. Results:
a. Treatment and mortality section:
i. As previously noted, the use of mean for the survival time variable is not appropriate because
this variable is subject to right-censoring. Please consult with a biostatistician with expertise in
survival analysis.
ii. What do the authors mean by death and lost of follow-up endpoints in the sentence “A total
of 101 patients experienced death and lost to follow-up endpoints”? Please clarify.
b. Analysis of factors associated with the prognostic impact of HH
i. The validity of the hazard ratios provided here rely on the proportional hazard assumption.
ii. Again, authors are using mean to summarize survival times, this is incorrect. Individuals
that haven’t died by the end of follow-up also provided information about survival time; this
information should be considered as well.
4. Discussion
a. The authors stated that “After multifactorial analysis, the findings indicated that liver
encephalopathy, hyponatremia, and MELD score were independent risk factors for prognostic
survival in HH”. Again, please avoid the term “risk factor” since these results come from an
exploratory analysis.
5. Tables
a. Table 3. Again, survival time is summarized as mean and standard deviation, this is incorrect.
b. Table 4. What variables were considered as confounders? Please specify.
c. Table 4. Did authors include in the same multivariate model the variables Hepatic
encephalopathy, Hyponatremia, Child–Pugh Score, MELD Score and MELD-Na Score? if
that is the case, the interpretation of the parameters is very complicated. For example, the
interpretation of the HR for MELD score would be “among individuals of the same gender,
same liver failure status, same hepatic encephalopathy status, same hyponatremia status, same
TBIL (umol/L) value, same PT (s), same Child–Pugh Score, same MELD-Na Score and same
ALBI Score, the HR for death comparing individuals who differ in their MELD score by 1 unit
is 1.063 95% CI (1.009, 1.121). It would be very hard to have individuals with different MELD-
score but who are identical in the other covariates included in the multivariate model.
Minor issues:
1. Abstract
d. A Cox regression assumes proportional hazards not proportional risks. Hazard and risks are
not the same.
e. The numbers provided are not mortality rates, they are cumulative mortalities. Please provide
the p-value for comparing the survival curves between men and women.
2. Methods
a. Study population section:
i. At the end of this section, it is stated that “Written informed consent was obtained from all
participants”, was this a general informed consent that the hospital obtains from all attended
patients or a specific informed consent for this study (very improbable in a retrospective study)?
Please clarify if the informed consent was specific for this study or a general informed consent
obtained from all patients attended at the hospital (in which case is usually waived by the Ethics
Committee).
b. Statistical analysis section:
i. What do authors mean by parametric continuous variables? My guess is that for each
continuous variable, the authors performed a test to assess if the data might follow a normal
distribution, and the variable was assumed as normally distributed when they failed to reject
the null hypothesis. If this is the case, please state it clearly and indicate the test for normality
that was used. Note: there are many parametric distribution for continuous variables: normal,
exponential, log-normal, gamma, chi-squared, etc.
3. Results
a. In general, please provide all numbers with only 2 or 3 significant digits. This will improve
the reading.
b. Demographics section:
i. The authors stated that “The prevalence of HH was 2.3%”. This number is not a prevalence
because HH were not assessed at a unique point in time. This number is only the proportion of
patients with cirrhosis diagnosis who developed HH at some time during an irregular follow-
up. The authors might compute the cumulative incidence of HH at a given time after cirrhosis
diagnosis or the overall incidence rate of HH by incorporating the time from cirrhosis diagnosis
to development of HH. These number would be meaningful. The provided number (2.3%) does
not represent a meaningful quantity and depends on the time patients the 5698 patients with
decompensated cirrhosis were followed-up.
ii. The authors stated that “HH was more common in men than in women”. This implies that the
proportion of men that developed HH among all men with decompensated cirrhosis is higher that
the proportion of women that developed HH among all women with decompensated cirrhosis.
However, these numbers are not provided. Please provide those numbers. Note: if the authors
were referring to the fact that the male-to-female ratio was 1.67:1 among the 131 individuals
with HH, this only imply that there were more males than females among the individuals with
HH, but it does not give any information about how common HH was among men or women.
c. Treatment and mortality section:
i. There is no need to provide the cumulative mortality at 30 days, 60 days, 90 days, 6 months,
1 year, 2 years, 3 years, 4 years and 5 years for males and females. The authors might refer the
reader to Figure 2.
ii. The authors stated that “it is clear that the mortality rate for males is significantly higher than
that for females at all time periods”. Please provide the p-value obtained from comparing the
survival curves.
d. Analysis of factors associated with the prognostic impact of HH
i. Define HR and CI only once.
4. Tables
a. All tables. Please provide all numbers with only 2 or 3 significant digits. This will improve
the reading.
5. Figures
a. Figure 2. The y axis label corresponds to “survival” or “survival probability” but not
cumulative survival. The x axis corresponds to time after HH diagnosis not survival. At each
time after the HH diagnosis the figure shows the survival probability at that time.
b. Figure 2. Values of p = 0.000 must be changed to p < 0.001.
c. Figure 2. Please provide the risk table below each plot.
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: 1 Date: 27 Apr 2022
Reviewer's report:
Thank you for the opportunity to review this manuscript. In this study, the authors describe the
characteristics at diagnosis and relevant outcomes during follow-up of a retrospective cohort of
131 individuals with cirrhosis and hepatic hydrothorax attended at a single hospital in China.
Although the topic is of high relevance due to the limited number of cohort studies on hepatic
hydrothorax, this study has major methodological issues than must be addressed to provide
good evidence. I strongly recommend the authors to consult a biostatistician with expertise in
survival analysis to perform the statistical analysis. I also recommend the authors to adhere to
the STROBE guidelines for cohort studies.
Major issues:
1. Abstract:
a. Being statistically significant in a multivariate Cox proportional hazard model does not imply
being an independent risk factor for death. Were confounders included in the model? Note:
being a confounder does not depend on a p-value from a univariate Cox regression; confounder
must be chosen a priori based on scientific knowledge. Also, I recommend avoiding the term
“risk factor” since these results come from an exploratory analysis (the authors performed many
hypothesis tests) and do not imply causality. Instead, they may word “factors associated with”.
b. When there are censored data, as is the case for survival here (30 individuals were alive at the
end of the study), the mean is not an appropriate measure of centrality for survival time.
2. Methods:
a. Outcomes section:
i. It is not clear the meaning of the sentence “Outcomes were death or and loss to follow-up as
endpoint events”. Since the authors performed a survival analysis, the outcome should be time
to death (a time to event type outcome). The time to death value for a patient who lost follow-
up is considered as right-censored.
b. Statistical analysis section:
i. Was the proportional hazard assumption assessed for each Cox regression model? Please
indicate how this assumption was assessed for univariate and multivariate models. The KM
survival curves suggests the assumption might not hold for some covariates. There are ways to
handle this, please consult a biostatistician.
ii. It is state that multivariate Cox regression models were adjusted for other confounders,
what other confounders? Please specify the confounders that were considered. Note: being a
confounder does not depend on a p-value from a univariate Cox regression; confounder must be
chosen a priori based on scientific knowledge.
3. Results:
a. Treatment and mortality section:
i. As previously noted, the use of mean for the survival time variable is not appropriate because
this variable is subject to right-censoring. Please consult with a biostatistician with expertise in
survival analysis.
ii. What do the authors mean by death and lost of follow-up endpoints in the sentence “A total
of 101 patients experienced death and lost to follow-up endpoints”? Please clarify.
b. Analysis of factors associated with the prognostic impact of HH
i. The validity of the hazard ratios provided here rely on the proportional hazard assumption.
ii. Again, authors are using mean to summarize survival times, this is incorrect. Individuals
that haven’t died by the end of follow-up also provided information about survival time; this
information should be considered as well.
4. Discussion
a. The authors stated that “After multifactorial analysis, the findings indicated that liver
encephalopathy, hyponatremia, and MELD score were independent risk factors for prognostic
survival in HH”. Again, please avoid the term “risk factor” since these results come from an
exploratory analysis.
5. Tables
a. Table 3. Again, survival time is summarized as mean and standard deviation, this is incorrect.
b. Table 4. What variables were considered as confounders? Please specify.
c. Table 4. Did authors include in the same multivariate model the variables Hepatic
encephalopathy, Hyponatremia, Child–Pugh Score, MELD Score and MELD-Na Score? if
that is the case, the interpretation of the parameters is very complicated. For example, the
interpretation of the HR for MELD score would be “among individuals of the same gender,
same liver failure status, same hepatic encephalopathy status, same hyponatremia status, same
TBIL (umol/L) value, same PT (s), same Child–Pugh Score, same MELD-Na Score and same
ALBI Score, the HR for death comparing individuals who differ in their MELD score by 1 unit
is 1.063 95% CI (1.009, 1.121). It would be very hard to have individuals with different MELD-
score but who are identical in the other covariates included in the multivariate model.
Minor issues:
1. Abstract
d. A Cox regression assumes proportional hazards not proportional risks. Hazard and risks are
not the same.
e. The numbers provided are not mortality rates, they are cumulative mortalities. Please provide
the p-value for comparing the survival curves between men and women.
2. Methods
a. Study population section:
i. At the end of this section, it is stated that “Written informed consent was obtained from all
participants”, was this a general informed consent that the hospital obtains from all attended
patients or a specific informed consent for this study (very improbable in a retrospective study)?
Please clarify if the informed consent was specific for this study or a general informed consent
obtained from all patients attended at the hospital (in which case is usually waived by the Ethics
Committee).
b. Statistical analysis section:
i. What do authors mean by parametric continuous variables? My guess is that for each
continuous variable, the authors performed a test to assess if the data might follow a normal
distribution, and the variable was assumed as normally distributed when they failed to reject
the null hypothesis. If this is the case, please state it clearly and indicate the test for normality
that was used. Note: there are many parametric distribution for continuous variables: normal,
exponential, log-normal, gamma, chi-squared, etc.
3. Results
a. In general, please provide all numbers with only 2 or 3 significant digits. This will improve
the reading.
b. Demographics section:
i. The authors stated that “The prevalence of HH was 2.3%”. This number is not a prevalence
because HH were not assessed at a unique point in time. This number is only the proportion of
patients with cirrhosis diagnosis who developed HH at some time during an irregular follow-
up. The authors might compute the cumulative incidence of HH at a given time after cirrhosis
diagnosis or the overall incidence rate of HH by incorporating the time from cirrhosis diagnosis
to development of HH. These number would be meaningful. The provided number (2.3%) does
not represent a meaningful quantity and depends on the time patients the 5698 patients with
decompensated cirrhosis were followed-up.
ii. The authors stated that “HH was more common in men than in women”. This implies that the
proportion of men that developed HH among all men with decompensated cirrhosis is higher that
the proportion of women that developed HH among all women with decompensated cirrhosis.
However, these numbers are not provided. Please provide those numbers. Note: if the authors
were referring to the fact that the male-to-female ratio was 1.67:1 among the 131 individuals
with HH, this only imply that there were more males than females among the individuals with
HH, but it does not give any information about how common HH was among men or women.
c. Treatment and mortality section:
i. There is no need to provide the cumulative mortality at 30 days, 60 days, 90 days, 6 months,
1 year, 2 years, 3 years, 4 years and 5 years for males and females. The authors might refer the
reader to Figure 2.
ii. The authors stated that “it is clear that the mortality rate for males is significantly higher than
that for females at all time periods”. Please provide the p-value obtained from comparing the
survival curves.
d. Analysis of factors associated with the prognostic impact of HH
i. Define HR and CI only once.
4. Tables
a. All tables. Please provide all numbers with only 2 or 3 significant digits. This will improve
the reading.
5. Figures
a. Figure 2. The y axis label corresponds to “survival” or “survival probability” but not
cumulative survival. The x axis corresponds to time after HH diagnosis not survival. At each
time after the HH diagnosis the figure shows the survival probability at that time.
b. Figure 2. Values of p = 0.000 must be changed to p < 0.001.
c. Figure 2. Please provide the risk table below each plot.
assistant