Health-Related Quality of Life in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Nationwide Population-Based Survey in Denmark

Round 1

Reviewer 1 Report

Thank you for the covering letter and the revised manuscript. However the manuscript is not substantially modified and my opinion remains the same. The conclusions of the survey are not very useful in the management of these patients and even could be misinterpreted.

Author Response

please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

It is unfortunate that they are not able to perform the further work I suggested which would make it a much more important paper but they explain that this is due to considerable logistical problems.

They have added further caveats on the data in the revised paper and overall

Author Response

please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

My opinion is that now the manuscript is suitable for publication.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

First of all this sudy present a mixed of very different diseases. It should be necessary to more differentiate the different MPN, the time since the diagnosis and the age at diagnosis. It is impossible to study simultaneously young ladies with ET since 2 years and older patients with MF secondary to ET or PV. Moreover it shoud be very important to study the role of the disease itself and the role of the treatment in the Qol of these patients.

MPN diagnosed in 1977 and those diagnosed after 2005 and the discovery of the mutations associated with MPN are not managed in the same way at all.

For these reasons the conclusions of this study are not very usefull for clinicians who manage patients with MPN.

For the reader it should be necessary to have in the manuscript hyperlinks to the different scores and scales used by the authors.

Author Response

Dear Reviewer

Thank you very much for the review. We appreciate that.

Please see below reply to the comments in italic;

First of all this sudy present a mixed of very different diseases. It should be necessary to more differentiate the different MPN, the time since the diagnosis and the age at diagnosis. It is impossible to study simultaneously young ladies with ET since 2 years and older patients with MF secondary to ET or PV.

It is a very good point that it might be different to be a patient with ET, PV, MF, and MPN-U respectively. The difference in HRQoL between these MPN subgroups in our cross-sectional survey was presented in this article.

The HRQoL data in this article were adjusted for age because we agree that the MPN disease might impact for example the young and elderly differently.

 It would be very interesting also to investigate if there is a potential difference in HRQoL between patients who have had the MPN diagnosis for different length of time. However, discovering the MPN diagnosis some time, possibly years, after the disease occurred seems to apply to quite a few patients, which could be challenging in this regard. Also, it would be very interesting to investigate if there is a difference in HRQoL between younger and elderly patients. These investigations could appropriately follow this presentation of cross-sectional HRQoL in the different MPN subgroups.

Moreover it shoud be very important to study the role of the disease itself and the role of the treatment in the Qol of these patients.

It is absolutely very important to investigate to which extent the MPN disease impacts QoL. Our intention was to investigate this by asking the participants about symptoms and QoL in this survey and present the answers. However, it would be very relevant also to investigate the association between different symptoms as well as symptom burden and QoL in future analyses on these survey data. To some extent we did this already in the published articles ´Anxiety and depression in patients with Philadelphia-negative myeloproliferative neoplasms: a nationwide population-based survey in Denmark´ and in ´Associations between fatigue, physical activity, and QoL in patients with myeloproliferative neoplasms´.

 It would indeed be very interesting to investigate the potential impact of treatment of haematological disease on HRQoL. It is unfortunately not possible to get to know which treatments the participants received at the time for participation in the survey or before by using a central register. Treatments of the haematological diesease are not registered centrally in Denmark like it is for example the case for the MPN diagnosis and comorbidity.

MPN diagnosed in 1977 and those diagnosed after 2005 and the discovery of the mutations associated with MPN are not managed in the same way at all.

For these reasons the conclusions of this study are not very usefull for clinicians who manage patients with MPN.

This is a cross-sectional survey where the subjects were asked to answer questions to their current HRQoL. We believe it would not be possible to investigate for HRQoL in the past for these subjects.

For the reader it should be necessary to have in the manuscript hyperlinks to the different scores and scales used by the authors.

The questionnaires, scores, and scales are unfortunately not available as hyperlinks. Instead, we included references to all questionnaires, scores, and scales in the first submitted version of the manuscript. Furthermore, all tables including questionnaires include description of the scores and scales used.

On behalf of the research group kind regards

Nana Brochmann

Reviewer 2 Report

This paper presents QoL data on a large number of MPN patients in a well resourced and developed single European country.  The institution and authors are well respected in this field. It is generally well written and presented. The QoL indices used are comprehensive and well validated particualrly the MPN-SAF. The overall results are somewhat contrarian to existing published data particularly with respect to comparisons to the general population. The inclusion of the MPNu group is novel and important. 

Comments:

1) The key issue is the validity of the 'general population' (GP) as the control group. There is liitle information given about the appropriateness and validity of this group. The Questionnaires were clearly not given to the 2 groups at a particular timepoint so they are not strictly matched groups. The authors must show a demographics comparison table with stats to prove that there is no significant difference between key demographics and lifestyle factors between the MPN and GP groups.

2) The sex ratio of MPN responders is the inverse of the sex ratio of MPN by incidence of the disorder so this could introduce bias ie the responders may  not be representative of MPN patients as a whole. 

3) This is a single timepoint data capture study with patients at all stages post diagnosis.  The majority of MPN patients had their diagnosis made > 5years prior to study. This is crucial because the study is therefore more about QoL in prevalent rather than incident disease and the results are therefore more likely to be skewed by treatment related factors. So it will be essential for the authors to compare the results from each of the 3 cohorts of time from diagnosis against their parameters. The results will be important whether different or not but will affect the the  interpretation of their results. 

4) Was data captured about patient treatment ?  If so, it would be useful to compare QoL between key treatments such as myelosuppressive agents versus not. 

5) The authors need to expand on why they believe their key comparison result of MPN vs GP QoL is so substantially different from most previous publications in this field. Although the differences were modest in most parameters, they were almost entirely highly statistically significant so this point needs emphasizing too. 

6) Similarly, the results in the MPNu cohort are essentially unique and need highlighting in both text and abstract. 

7) In the light of the outcome of the above further analyses and response to other concerns, the abstract needs major revision. 

Author Response

Dear Reviewer

Thank you very much for the review. We appreciate that.

Please see below reply to the comments in italic;

1) The key issue is the validity of the 'general population' (GP) as the control group. There is liitle information given about the appropriateness and validity of this group.

Thank you for the good comment. For clarity, more detailed information about when the surveys used for comparison were conducted have now been included in the manuscript.

The general population lifestyle data used for comorbidity comparison were collected from the Danish population in the spring 2013 by the Danish National Institute of Public Health (NIPH). Please see the methods section in the manuscript and reference 49. The Danish population reference data for the questionnaire EORTC QLQ C30 used for HRQoL comparison were collected Oct 2012 – Mar 2013. Please see the methods section in the manuscript and reference 50. The MPNhealthSurvey took place in autumn 2013.

The Questionnaires were clearly not given to the 2 groups at a particular timepoint so they are not strictly matched groups. The authors must show a demographics comparison table with stats to prove that there is no significant difference between key demographics and lifestyle factors between the MPN and GP groups.

We do not currently have access to the general population data made available by the NIPH and used for comparison of comorbidity. Using the general population data for the reviewer requested purpose would require new legal arrangements in accordance with the Danish implementation of the European Union General Data Protection Regulation between NIPH and the research group. This might be possible, but it will take several months and possibly even longer. We can therefore not meet the query to do a demographics comparison table which stats to prove that there is no significant difference between key demographics and lifestyle factors between the MPN and the general population group.

The results of the EORTC QLQ C30 questionnaire survey on a general Danish population are available in an article that presents the data. We do not have access to the survey database. Please see reference 50.

The general population sample used for comparison was age and sex matched to the survey population. We believe that differences in lifestyle are interesting because it could at least to some extent reflect differences between the MPN survey population and the general population that are caused by having a MPN disease and not having a MPN disease, respectively, and this might also have impact on HRQoL. We believe, however, that differences in lifestyle between the MPN survey population and the general population used for comparison need to be highlighted rather than adjusted for.

2) The sex ratio of MPN responders is the inverse of the sex ratio of MPN by incidence of the disorder so this could introduce bias ie the responders may  not be representative of MPN patients as a whole. 

We agree, this is important. Of note, we adjusted for sex when we compared the HRQoL between the different MPN subgroups, and the general population group was sex matched to the survey population.

3) This is a single timepoint data capture study with patients at all stages post diagnosis.  The majority of MPN patients had their diagnosis made > 5years prior to study. This is crucial because the study is therefore more about QoL in prevalent rather than incident disease and the results are therefore more likely to be skewed by treatment related factors. So it will be essential for the authors to compare the results from each of the 3 cohorts of time from diagnosis against their parameters. The results will be important whether different or not but will affect the the  interpretation of their results. 

Thank you for sharing this important consideration. We assume that the parameters which the reviewer refers to are results of blood sample analysis. Investigating for potential difference in association between HRQoL results and results of blood sample analysis between the MPN subgroups would indeed be interesting and clinically relevant information. Unfortunately, we do not have a central access to results of blood analyses in Denmark, and thus we are not able to collect results of blood analyses for this large population where the patients are affiliated with different haematological clinics in Denmark.

4) Was data captured about patient treatment ?  If so, it would be useful to compare QoL between key treatments such as myelosuppressive agents versus not. 

It is unfortunately not possible to get to know which treatments the participants received at the time for participation in the survey or before this by using a central register. Treatments of the haematological diesease are not registered in a central register in Denmark like it is for example the case for the MPN diagnosis and comorbidity.

5) The authors need to expand on why they believe their key comparison result of MPN vs GP QoL is so substantially different from most previous publications in this field. Although the differences were modest in most parameters, they were almost entirely highly statistically significant so this point needs emphasizing too. 

Thank you for making us aware of the importance of discussing our results in this regard. We have discussed this further in the discussion section.

We intended to follow the newest recommendations from International Society for Quality of Life Research for assessing difference in HRQoL between groups. According to these recommendations clinically significant difference should attach the attention rather than statistically significant difference. We hope for understanding of our choice taking this approach.

6) Similarly, the results in the MPNu cohort are essentially unique and need highlighting in both text and abstract. 

Thank you for making us aware of the importance of highlighting this. We did this in the text and abstract.

7) In the light of the outcome of the above further analyses and response to other concerns, the abstract needs major revision. 

Thank you for noticing this. We have updated the abstract accordingly. However, no further analyses have been performed and the reason for this is explained above.

On behalf of the research groups kind regards

Nana Brochmann