Reviewer ’s report  
 
Title: Cost-comparison an alysis of FIB -4, ELF and fibroscan  in community pathways for Non - 
Alcoholic Fatty Liver Disease  
 
Version: 0 Date: 19 Jan 2019  
 
Reviewer: Elliot Tapper  
 
Reviewer's report:  
This is an important paper but the methods need substantial attention. This reviewer is very 
supportive and therefore left several constructive criticisms  
Test characteristics:  
a) the authors use point -estimates without beta or triangular distributions. T his limits the 
probabilistic decision model.  
b) Where is liver biopsy utilized, this reviewer cannot find it in the methods.  
c) Is liver biopsy assumed to be perfect? Without risk?  
d) The performance of sequential tests impacts the PPV/NPV of the second  test, have they 
discussed how this was determined.  
Outcome:  
A) "cost -effectiveness" is really "cost -utility". The cost per "F3" detected has no standard by 
which to adjudicate the value, there is no "willingness to pay" per incremental "F3". These 
descri ptive data need contextualization (i.e. Cost/QALY) or acknowledging the limit.  
B) The authors also present "Total expenditures" - would recommend discussing a "budget 
impact model" and phrasing things in increments.  
C) All these data need to be reframed in increments vis -à-vis SOC as a referent baseline, how 
many more (or less) people are correctly classified, how much more (or less) is spent.  
D) The long term outcomes are somewhat pie -in-the sky. Would strongly recommend presenting 
clear data - not the bar charts - on the incremental correct classifications, the incremental 
impact on referrals, and costs/visits within year 1. This model will be strongest for 
determining these early outcomes.  
False positives - this reviewer feels that many of the misclass ified persons have incurred 
tremendous costs (imaging, endoscopy, and even biopsy) and these harms have not been 
explored, quantified. Could they be BETTER with NILT than SOC? Perhaps. Show us please 
using incremental values. The bar chart asserts a lower level of misclassification but this needs 
some work to help this reviewer.  
I) the proportion misclassified as F3 is lower in scenario 1 of fig 3 than in the bar chart, is 
this my misunderstanding?  
II) ) What are we assuming that SOC means that after referr al to specialist, that the patient is 
treated as F3 forevermore?  
Costs -  
A) There are many costs in the model - US, MRI, biopsy - but the scenarios when they are used 
are not clear to this reviewer.  
B) The costs are best described as direct costs and the  MRI for 100 pounds is a bit low. Direct 
cost of the MRI scan is greater - time of tech, radiologist, opportunity costs, etc and I think 
the estimate understates these things. The solution is not to present the ridiculous "charges" 
seen in other studies bu t this reviewer thinks the costs are too low.  
Probabilistic models - this reviewer does not see any mention of ranges/errors and for this reason 
I do not believe that a true PSA was performed. Note that, as above, we cannot deterimine a 
'cost-acceptability ' curve because there is fundamentally no normative (e.g. WTP threshold) data 
even asserted.  
 
Additional Methods  
- Cycle length?  
- Discount rate?  
- How are patients with NAFLD identified in SOC? Is this assumed to be accurate?  
Compensated cirrhosis  
- 0.10 prob of HCC too high (substantially)  
- 0.08 mortality best linked to age (it is much lower at 50 than 55, 60, etc)  
- What is the risk of varices in a cohort with VCTE 7.9 in 5 years? Likely <0.19. Varices 
needing treatment? <<<<0.19  
Minor  
Figure 5 - This reviewer is sympathetic given how much work went into presenting these 
numbers but they are best re -phrased as incremental costs.  
State transition model - does not include regression of stages  
Reviewer ’s report  
 
Title: Cost-comparison an alysis of FIB -4, ELF and fibroscan  in community pathways for Non - 
Alcoholic Fatty Liver Disease  
 
Version: 0 Date: 19 Jan 2019  
 
Reviewer: Elliot Tapper  
 
Reviewer's report:  
This is an important paper but the methods need substantial attention. This reviewer is very 
supportive and therefore left several constructive criticisms  
Test characteristics:  
a) the authors use point -estimates without beta or triangular distributions. T his limits the 
probabilistic decision model.  
b) Where is liver biopsy utilized, this reviewer cannot find it in the methods.  
c) Is liver biopsy assumed to be perfect? Without risk?  
d) The performance of sequential tests impacts the PPV/NPV of the second  test, have they 
discussed how this was determined.  
Outcome:  
A) "cost -effectiveness" is really "cost -utility". The cost per "F3" detected has no standard by 
which to adjudicate the value, there is no "willingness to pay" per incremental "F3". These 
descri ptive data need contextualization (i.e. Cost/QALY) or acknowledging the limit.  
B) The authors also present "Total expenditures" - would recommend discussing a "budget 
impact model" and phrasing things in increments.  
C) All these data need to be reframed in increments vis -à-vis SOC as a referent baseline, how 
many more (or less) people are correctly classified, how much more (or less) is spent.  
D) The long term outcomes are somewhat pie -in-the sky. Would strongly recommend presenting 
clear data - not the bar charts - on the incremental correct classifications, the incremental 
impact on referrals, and costs/visits within year 1. This model will be strongest for 
determining these early outcomes.  
False positives - this reviewer feels that many of the misclass ified persons have incurred 
tremendous costs (imaging, endoscopy, and even biopsy) and these harms have not been 
explored, quantified. Could they be BETTER with NILT than SOC? Perhaps. Show us please 
using incremental values. The bar chart asserts a lower level of misclassification but this needs 
some work to help this reviewer.  
I) the proportion misclassified as F3 is lower in scenario 1 of fig 3 than in the bar chart, is 
this my misunderstanding?  
II) ) What are we assuming that SOC means that after referr al to specialist, that the patient is 
treated as F3 forevermore?  
Costs -  
A) There are many costs in the model - US, MRI, biopsy - but the scenarios when they are used 
are not clear to this reviewer.  
B) The costs are best described as direct costs and the  MRI for 100 pounds is a bit low. Direct 
cost of the MRI scan is greater - time of tech, radiologist, opportunity costs, etc and I think 
the estimate understates these things. The solution is not to present the ridiculous "charges" 
seen in other studies bu t this reviewer thinks the costs are too low.  
Probabilistic models - this reviewer does not see any mention of ranges/errors and for this reason 
I do not believe that a true PSA was performed. Note that, as above, we cannot deterimine a 
'cost-acceptability ' curve because there is fundamentally no normative (e.g. WTP threshold) data 
even asserted.  
 
Additional Methods  
- Cycle length?  
- Discount rate?  
- How are patients with NAFLD identified in SOC? Is this assumed to be accurate?  
Compensated cirrhosis  
- 0.10 prob of HCC too high (substantially)  
- 0.08 mortality best linked to age (it is much lower at 50 than 55, 60, etc)  
- What is the risk of varices in a cohort with VCTE 7.9 in 5 years? Likely <0.19. Varices 
needing treatment? <<<<0.19  
Minor  
Figure 5 - This reviewer is sympathetic given how much work went into presenting these 
numbers but they are best re -phrased as incremental costs.  
State transition model - does not include regression of stages  
Please review this paper.
user
Reviewer ’s report  
 
Title: Cost-comparison an alysis of FIB -4, ELF and fibroscan  in community pathways for Non - 
Alcoholic Fatty Liver Disease  
 
Version: 0 Date: 19 Jan 2019  
 
Reviewer: Elliot Tapper  
 
Reviewer's report:  
This is an important paper but the methods need substantial attention. This reviewer is very 
supportive and therefore left several constructive criticisms  
Test characteristics:  
a) the authors use point -estimates without beta or triangular distributions. T his limits the 
probabilistic decision model.  
b) Where is liver biopsy utilized, this reviewer cannot find it in the methods.  
c) Is liver biopsy assumed to be perfect? Without risk?  
d) The performance of sequential tests impacts the PPV/NPV of the second  test, have they 
discussed how this was determined.  
Outcome:  
A) "cost -effectiveness" is really "cost -utility". The cost per "F3" detected has no standard by 
which to adjudicate the value, there is no "willingness to pay" per incremental "F3". These 
descri ptive data need contextualization (i.e. Cost/QALY) or acknowledging the limit.  
B) The authors also present "Total expenditures" - would recommend discussing a "budget 
impact model" and phrasing things in increments.  
C) All these data need to be reframed in increments vis -à-vis SOC as a referent baseline, how 
many more (or less) people are correctly classified, how much more (or less) is spent.  
D) The long term outcomes are somewhat pie -in-the sky. Would strongly recommend presenting 
clear data - not the bar charts - on the incremental correct classifications, the incremental 
impact on referrals, and costs/visits within year 1. This model will be strongest for 
determining these early outcomes.  
False positives - this reviewer feels that many of the misclass ified persons have incurred 
tremendous costs (imaging, endoscopy, and even biopsy) and these harms have not been 
explored, quantified. Could they be BETTER with NILT than SOC? Perhaps. Show us please 
using incremental values. The bar chart asserts a lower level of misclassification but this needs 
some work to help this reviewer.  
I) the proportion misclassified as F3 is lower in scenario 1 of fig 3 than in the bar chart, is 
this my misunderstanding?  
II) ) What are we assuming that SOC means that after referr al to specialist, that the patient is 
treated as F3 forevermore?  
Costs -  
A) There are many costs in the model - US, MRI, biopsy - but the scenarios when they are used 
are not clear to this reviewer.  
B) The costs are best described as direct costs and the  MRI for 100 pounds is a bit low. Direct 
cost of the MRI scan is greater - time of tech, radiologist, opportunity costs, etc and I think 
the estimate understates these things. The solution is not to present the ridiculous "charges" 
seen in other studies bu t this reviewer thinks the costs are too low.  
Probabilistic models - this reviewer does not see any mention of ranges/errors and for this reason 
I do not believe that a true PSA was performed. Note that, as above, we cannot deterimine a 
'cost-acceptability ' curve because there is fundamentally no normative (e.g. WTP threshold) data 
even asserted.  
 
Additional Methods  
- Cycle length?  
- Discount rate?  
- How are patients with NAFLD identified in SOC? Is this assumed to be accurate?  
Compensated cirrhosis  
- 0.10 prob of HCC too high (substantially)  
- 0.08 mortality best linked to age (it is much lower at 50 than 55, 60, etc)  
- What is the risk of varices in a cohort with VCTE 7.9 in 5 years? Likely <0.19. Varices 
needing treatment? <<<<0.19  
Minor  
Figure 5 - This reviewer is sympathetic given how much work went into presenting these 
numbers but they are best re -phrased as incremental costs.  
State transition model - does not include regression of stages  
assistant