Title: Platelet Derived Growth Factor Receptor-# as a Non-Invasive Biomarker for Liver
Fibrosis Prediction in Diabetic Non-alcoholic Fatty Liver Disease
Version: 2 Date: 06 Nov 2024
Reviewer:  Amira A A Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work. In this study, Badran et al in this research aimed
to evaluate the productivity of serum PDGFR# as a non-invasive biomarker of liver fibrosis in
diabetic MAFLD patients.
Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver
disease, is a prevalent condition characterized by hepatic steatosis and can progress to more
severe stages such as liver fibrosis, cirrhosis, and even hepatocellular carcinoma*. MAFLD has
emerged as a global health concern, affecting 25% of the global population**. The prevalence of
MAFLD is increasing yearly owing to changes in diet, lifestyle, and health conditions***. Liver
fibrosis is the major determinant of adverse outcomes in patients with MAFLD****. Hence,
early and accurate identification of patients with fibrosis is essential.
(*: Doi: 10.1053/j.gastro.2019.11.312, **: Doi: 10.1210/clinem/dgac321, ***: Doi: 10.1038/
s41575-020-00381-6, ****: doi: 10.1016/j.clinre.2022.102063)
The authors handled the reviewer comments satisfactorily, nevertheless, there is an observation
for which sufficient justification must be obtained.
In general:
1. The study found significantly higher PDGFR# levels in both diabetic and non-diabetic
MAFLD patients compared to controls. This suggests that PDGFR# is a reliable indicator of
liver fibrosis severity. The sensitivity, specificity, positive predictive value (PPV), and negative
predictive value (NPV) of PDGFR# to predict significant liver fibrosis in diabetic MAFLD
patients were 85%, 93.33%, 89.5%, and 90.3%, respectively, at a cutoff > 2.54. These values
indicate a high diagnostic accuracy. The combination of PDGFR# at a cutoff > 2.54 and FIB-4 at
a cutoff > 1.17 resulted in 100% sensitivity, specificity, PPV, and NPV for predicting significant
liver fibrosis in diabetic MAFLD patients. Such findings may indicate the reduced need for
invasive liver biopsies. Additionally, PDGFR# could complement other non-invasive scores and
imaging modalities, providing a more comprehensive assessment of liver fibrosis.
In Title:
2. The authors should mention the country in which the study was performed.
In Abstract section
3. The background subsection:
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject and hence what the study intended to examine (or what the paper seeks to
present). Please reconstruct it properly.
4.  The type of study: a population-based study.
5. In method subsection:
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
In the Introduction section:
6. In contrast to NAFLD, MAFLD does not necessitate ruling out other liver disease causes,
such as viral hepatitis or heavy alcohol use*. The new name chosen to replace NAFLD reflected
the disease etiology better and conveyed a more practical approach in daily clinical practice than
NAFLD, considering its close association with metabolic syndrome**. Please discuss the new
nomenclature in more detail.
(*: Doi: 10.1016/j.jhep.2020.03.039, **: doi: 10.1097/HEP.0000000000000520)
In the Methods section:
7. Ethics approval data must be provided in the methodology section.
8. Please provide the participants' sociodemographic data.
9. How the sample size was calculated.
10. Inclusion and exclusion criteria are incomplete.
11. How were patients with T2DM diagnosed?
12. All data were prospectively collected. No data were collected retrospectively?
13. The studied parameters should include:
• Epidemiological data: age, gender, profession, etc.
• Clinical data: symptoms presentation and their duration, existence of metabolic risk factor
(obesity, dyslipidemia, hypertension), alcohol and tobacco use, contraception, blood pressure,
systolic pressure index, temperature, heart rate, respiratory rate, weight, height, body mass index,
waist circumference, etc.
• Paraclinical data: hepatic test (SGOT, SGPT, prothrombin time), fasting blood glucose,
hemoglobin (anemia), hematocrit (hemoconcentration), white blood cell (leukocytosis),
creatinine level, imaging modality (ultrasonography, CT scan, MRI,…), biomarkers, etc.
• Therapeutic data: type of treatment (medical treatment).
14. Statistical analysis:
- The Mann–Whitney U test is a nonparametric test and involves the summation of ranks. The
Mann–Whitney U test is applied to independent samples. T-test is used to compare the mean of
a continuous variable between a maximum of 2 groups. The Kruskal–Wallis test is a statistical
test used to compare two or more groups for a continuous or discrete variable. The Wilcoxon
rank-sum test is used to compare two independent samples, while the Wilcoxon signed-rank
test is used to compare two related samples, matched samples, or to conduct a paired difference
test of repeated measurements on a single sample to assess whether their population mean ranks
differ. How did you choose the proper test during your result analysis?
In the Results section:
15. By concentrating exclusively on diabetic MAFLD patients, this study distinguishes itself
from others on non-invasive indicators for liver fibrosis. Non-invasive diagnostics designed for
non-diabetic populations frequently have poor performance in diabetic patients, according to
prior research. This study closes this gap by showing that PDGFR# predicts severe liver fibrosis
in diabetic MAFLD patients more accurately, particularly when paired with the FIB-4 score.
In the Discussion section:
16. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
17. The study's limitations are the small sample size, single-center methodology, and absence of
comparison with other well-established biomarkers. To validate these findings, future research
should concentrate on larger, multi-center investigations. Long-term tracking of PDGFR# levels
in connection to clinical outcomes and comparisons with other biomarkers are also required. A
more conclusive evaluation of liver fibrosis would also be possible with the inclusion of a liver
biopsy in subsequent research.
18. The study strengths should also be provided.
For example:
- Using PDGFR# as a biomarker could improve non-invasive detection of liver fibrosis in
diabetic MAFLD patients overcoming the limits of current biomarkers in this patient population.
- The study used a strong case-control design with diabetic MAFLD patients, non-diabetic
MAFLD patients, and healthy controls, enabling accurate comparison and validation of
PDGFR# as a biomarker.
- The findings are validated using a variety of statistical methods, including multivariate logistic
regression, increasing the dependability of the findings.
- The findings have important clinical implications since they provide a more reliable non-
invasive diagnostic tool for liver fibrosis in diabetic MAFLD patients, minimizing the need for
invasive liver biopsies.
- etc.
19. The discussion should explain how MAFLD can be managed in Egypt (Doi: 10.4103/
sjg.sjg_357_21).
20. Discuss the novelty of your study in the notion of previous studies (DOI: 10.1016/
j.ebiom.2019.04.036).
In the conclusion section:
21. The conclusion should restate your main points and provide closure. Please reconstruct.
For example: The study suggests that PDGFR# is a highly sensitive and selective non-invasive
biomarker for diagnosing liver fibrosis in diabetic MAFLD patients. The inclusion of PDGFR#
in the FIB-4 score improves diagnostic performance and may reduce the necessity for invasive
liver biopsies.
Title: Platelet Derived Growth Factor Receptor-# as a Non-Invasive Biomarker for Liver
Fibrosis Prediction in Diabetic Non-alcoholic Fatty Liver Disease
Version: 2 Date: 06 Nov 2024
Reviewer:  Amira A A Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work. In this study, Badran et al in this research aimed
to evaluate the productivity of serum PDGFR# as a non-invasive biomarker of liver fibrosis in
diabetic MAFLD patients.
Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver
disease, is a prevalent condition characterized by hepatic steatosis and can progress to more
severe stages such as liver fibrosis, cirrhosis, and even hepatocellular carcinoma*. MAFLD has
emerged as a global health concern, affecting 25% of the global population**. The prevalence of
MAFLD is increasing yearly owing to changes in diet, lifestyle, and health conditions***. Liver
fibrosis is the major determinant of adverse outcomes in patients with MAFLD****. Hence,
early and accurate identification of patients with fibrosis is essential.
(*: Doi: 10.1053/j.gastro.2019.11.312, **: Doi: 10.1210/clinem/dgac321, ***: Doi: 10.1038/
s41575-020-00381-6, ****: doi: 10.1016/j.clinre.2022.102063)
The authors handled the reviewer comments satisfactorily, nevertheless, there is an observation
for which sufficient justification must be obtained.
In general:
1. The study found significantly higher PDGFR# levels in both diabetic and non-diabetic
MAFLD patients compared to controls. This suggests that PDGFR# is a reliable indicator of
liver fibrosis severity. The sensitivity, specificity, positive predictive value (PPV), and negative
predictive value (NPV) of PDGFR# to predict significant liver fibrosis in diabetic MAFLD
patients were 85%, 93.33%, 89.5%, and 90.3%, respectively, at a cutoff > 2.54. These values
indicate a high diagnostic accuracy. The combination of PDGFR# at a cutoff > 2.54 and FIB-4 at
a cutoff > 1.17 resulted in 100% sensitivity, specificity, PPV, and NPV for predicting significant
liver fibrosis in diabetic MAFLD patients. Such findings may indicate the reduced need for
invasive liver biopsies. Additionally, PDGFR# could complement other non-invasive scores and
imaging modalities, providing a more comprehensive assessment of liver fibrosis.
In Title:
2. The authors should mention the country in which the study was performed.
In Abstract section
3. The background subsection:
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject and hence what the study intended to examine (or what the paper seeks to
present). Please reconstruct it properly.
4.  The type of study: a population-based study.
5. In method subsection:
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
In the Introduction section:
6. In contrast to NAFLD, MAFLD does not necessitate ruling out other liver disease causes,
such as viral hepatitis or heavy alcohol use*. The new name chosen to replace NAFLD reflected
the disease etiology better and conveyed a more practical approach in daily clinical practice than
NAFLD, considering its close association with metabolic syndrome**. Please discuss the new
nomenclature in more detail.
(*: Doi: 10.1016/j.jhep.2020.03.039, **: doi: 10.1097/HEP.0000000000000520)
In the Methods section:
7. Ethics approval data must be provided in the methodology section.
8. Please provide the participants' sociodemographic data.
9. How the sample size was calculated.
10. Inclusion and exclusion criteria are incomplete.
11. How were patients with T2DM diagnosed?
12. All data were prospectively collected. No data were collected retrospectively?
13. The studied parameters should include:
• Epidemiological data: age, gender, profession, etc.
• Clinical data: symptoms presentation and their duration, existence of metabolic risk factor
(obesity, dyslipidemia, hypertension), alcohol and tobacco use, contraception, blood pressure,
systolic pressure index, temperature, heart rate, respiratory rate, weight, height, body mass index,
waist circumference, etc.
• Paraclinical data: hepatic test (SGOT, SGPT, prothrombin time), fasting blood glucose,
hemoglobin (anemia), hematocrit (hemoconcentration), white blood cell (leukocytosis),
creatinine level, imaging modality (ultrasonography, CT scan, MRI,…), biomarkers, etc.
• Therapeutic data: type of treatment (medical treatment).
14. Statistical analysis:
- The Mann–Whitney U test is a nonparametric test and involves the summation of ranks. The
Mann–Whitney U test is applied to independent samples. T-test is used to compare the mean of
a continuous variable between a maximum of 2 groups. The Kruskal–Wallis test is a statistical
test used to compare two or more groups for a continuous or discrete variable. The Wilcoxon
rank-sum test is used to compare two independent samples, while the Wilcoxon signed-rank
test is used to compare two related samples, matched samples, or to conduct a paired difference
test of repeated measurements on a single sample to assess whether their population mean ranks
differ. How did you choose the proper test during your result analysis?
In the Results section:
15. By concentrating exclusively on diabetic MAFLD patients, this study distinguishes itself
from others on non-invasive indicators for liver fibrosis. Non-invasive diagnostics designed for
non-diabetic populations frequently have poor performance in diabetic patients, according to
prior research. This study closes this gap by showing that PDGFR# predicts severe liver fibrosis
in diabetic MAFLD patients more accurately, particularly when paired with the FIB-4 score.
In the Discussion section:
16. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
17. The study's limitations are the small sample size, single-center methodology, and absence of
comparison with other well-established biomarkers. To validate these findings, future research
should concentrate on larger, multi-center investigations. Long-term tracking of PDGFR# levels
in connection to clinical outcomes and comparisons with other biomarkers are also required. A
more conclusive evaluation of liver fibrosis would also be possible with the inclusion of a liver
biopsy in subsequent research.
18. The study strengths should also be provided.
For example:
- Using PDGFR# as a biomarker could improve non-invasive detection of liver fibrosis in
diabetic MAFLD patients overcoming the limits of current biomarkers in this patient population.
- The study used a strong case-control design with diabetic MAFLD patients, non-diabetic
MAFLD patients, and healthy controls, enabling accurate comparison and validation of
PDGFR# as a biomarker.
- The findings are validated using a variety of statistical methods, including multivariate logistic
regression, increasing the dependability of the findings.
- The findings have important clinical implications since they provide a more reliable non-
invasive diagnostic tool for liver fibrosis in diabetic MAFLD patients, minimizing the need for
invasive liver biopsies.
- etc.
19. The discussion should explain how MAFLD can be managed in Egypt (Doi: 10.4103/
sjg.sjg_357_21).
20. Discuss the novelty of your study in the notion of previous studies (DOI: 10.1016/
j.ebiom.2019.04.036).
In the conclusion section:
21. The conclusion should restate your main points and provide closure. Please reconstruct.
For example: The study suggests that PDGFR# is a highly sensitive and selective non-invasive
biomarker for diagnosing liver fibrosis in diabetic MAFLD patients. The inclusion of PDGFR#
in the FIB-4 score improves diagnostic performance and may reduce the necessity for invasive
liver biopsies.
Please review this paper.
user
Title: Platelet Derived Growth Factor Receptor-# as a Non-Invasive Biomarker for Liver
Fibrosis Prediction in Diabetic Non-alcoholic Fatty Liver Disease
Version: 2 Date: 06 Nov 2024
Reviewer:  Amira A A Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work. In this study, Badran et al in this research aimed
to evaluate the productivity of serum PDGFR# as a non-invasive biomarker of liver fibrosis in
diabetic MAFLD patients.
Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver
disease, is a prevalent condition characterized by hepatic steatosis and can progress to more
severe stages such as liver fibrosis, cirrhosis, and even hepatocellular carcinoma*. MAFLD has
emerged as a global health concern, affecting 25% of the global population**. The prevalence of
MAFLD is increasing yearly owing to changes in diet, lifestyle, and health conditions***. Liver
fibrosis is the major determinant of adverse outcomes in patients with MAFLD****. Hence,
early and accurate identification of patients with fibrosis is essential.
(*: Doi: 10.1053/j.gastro.2019.11.312, **: Doi: 10.1210/clinem/dgac321, ***: Doi: 10.1038/
s41575-020-00381-6, ****: doi: 10.1016/j.clinre.2022.102063)
The authors handled the reviewer comments satisfactorily, nevertheless, there is an observation
for which sufficient justification must be obtained.
In general:
1. The study found significantly higher PDGFR# levels in both diabetic and non-diabetic
MAFLD patients compared to controls. This suggests that PDGFR# is a reliable indicator of
liver fibrosis severity. The sensitivity, specificity, positive predictive value (PPV), and negative
predictive value (NPV) of PDGFR# to predict significant liver fibrosis in diabetic MAFLD
patients were 85%, 93.33%, 89.5%, and 90.3%, respectively, at a cutoff > 2.54. These values
indicate a high diagnostic accuracy. The combination of PDGFR# at a cutoff > 2.54 and FIB-4 at
a cutoff > 1.17 resulted in 100% sensitivity, specificity, PPV, and NPV for predicting significant
liver fibrosis in diabetic MAFLD patients. Such findings may indicate the reduced need for
invasive liver biopsies. Additionally, PDGFR# could complement other non-invasive scores and
imaging modalities, providing a more comprehensive assessment of liver fibrosis.
In Title:
2. The authors should mention the country in which the study was performed.
In Abstract section
3. The background subsection:
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject and hence what the study intended to examine (or what the paper seeks to
present). Please reconstruct it properly.
4.  The type of study: a population-based study.
5. In method subsection:
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
In the Introduction section:
6. In contrast to NAFLD, MAFLD does not necessitate ruling out other liver disease causes,
such as viral hepatitis or heavy alcohol use*. The new name chosen to replace NAFLD reflected
the disease etiology better and conveyed a more practical approach in daily clinical practice than
NAFLD, considering its close association with metabolic syndrome**. Please discuss the new
nomenclature in more detail.
(*: Doi: 10.1016/j.jhep.2020.03.039, **: doi: 10.1097/HEP.0000000000000520)
In the Methods section:
7. Ethics approval data must be provided in the methodology section.
8. Please provide the participants' sociodemographic data.
9. How the sample size was calculated.
10. Inclusion and exclusion criteria are incomplete.
11. How were patients with T2DM diagnosed?
12. All data were prospectively collected. No data were collected retrospectively?
13. The studied parameters should include:
• Epidemiological data: age, gender, profession, etc.
• Clinical data: symptoms presentation and their duration, existence of metabolic risk factor
(obesity, dyslipidemia, hypertension), alcohol and tobacco use, contraception, blood pressure,
systolic pressure index, temperature, heart rate, respiratory rate, weight, height, body mass index,
waist circumference, etc.
• Paraclinical data: hepatic test (SGOT, SGPT, prothrombin time), fasting blood glucose,
hemoglobin (anemia), hematocrit (hemoconcentration), white blood cell (leukocytosis),
creatinine level, imaging modality (ultrasonography, CT scan, MRI,…), biomarkers, etc.
• Therapeutic data: type of treatment (medical treatment).
14. Statistical analysis:
- The Mann–Whitney U test is a nonparametric test and involves the summation of ranks. The
Mann–Whitney U test is applied to independent samples. T-test is used to compare the mean of
a continuous variable between a maximum of 2 groups. The Kruskal–Wallis test is a statistical
test used to compare two or more groups for a continuous or discrete variable. The Wilcoxon
rank-sum test is used to compare two independent samples, while the Wilcoxon signed-rank
test is used to compare two related samples, matched samples, or to conduct a paired difference
test of repeated measurements on a single sample to assess whether their population mean ranks
differ. How did you choose the proper test during your result analysis?
In the Results section:
15. By concentrating exclusively on diabetic MAFLD patients, this study distinguishes itself
from others on non-invasive indicators for liver fibrosis. Non-invasive diagnostics designed for
non-diabetic populations frequently have poor performance in diabetic patients, according to
prior research. This study closes this gap by showing that PDGFR# predicts severe liver fibrosis
in diabetic MAFLD patients more accurately, particularly when paired with the FIB-4 score.
In the Discussion section:
16. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
17. The study's limitations are the small sample size, single-center methodology, and absence of
comparison with other well-established biomarkers. To validate these findings, future research
should concentrate on larger, multi-center investigations. Long-term tracking of PDGFR# levels
in connection to clinical outcomes and comparisons with other biomarkers are also required. A
more conclusive evaluation of liver fibrosis would also be possible with the inclusion of a liver
biopsy in subsequent research.
18. The study strengths should also be provided.
For example:
- Using PDGFR# as a biomarker could improve non-invasive detection of liver fibrosis in
diabetic MAFLD patients overcoming the limits of current biomarkers in this patient population.
- The study used a strong case-control design with diabetic MAFLD patients, non-diabetic
MAFLD patients, and healthy controls, enabling accurate comparison and validation of
PDGFR# as a biomarker.
- The findings are validated using a variety of statistical methods, including multivariate logistic
regression, increasing the dependability of the findings.
- The findings have important clinical implications since they provide a more reliable non-
invasive diagnostic tool for liver fibrosis in diabetic MAFLD patients, minimizing the need for
invasive liver biopsies.
- etc.
19. The discussion should explain how MAFLD can be managed in Egypt (Doi: 10.4103/
sjg.sjg_357_21).
20. Discuss the novelty of your study in the notion of previous studies (DOI: 10.1016/
j.ebiom.2019.04.036).
In the conclusion section:
21. The conclusion should restate your main points and provide closure. Please reconstruct.
For example: The study suggests that PDGFR# is a highly sensitive and selective non-invasive
biomarker for diagnosing liver fibrosis in diabetic MAFLD patients. The inclusion of PDGFR#
in the FIB-4 score improves diagnostic performance and may reduce the necessity for invasive
liver biopsies.
assistant