Author's response to reviews Title: Diabetes duration and health-related quality of life in individuals with onset of diabetes in the age group 15-34 years - a Swedish population-based study using EQ-5D Authors: Vibeke Sparring (vibeke.sparring@ki.se) Lennarth Nyström (lennarth.nystrom@epiph.umu.se) Rolf Wahlström (rolf.wahlstrom@ki.se) Pia Maria Jonsson (pia.maria.jonsson@thl.fi) Jan Östman (jan.j.c.oestman@solna.mail.telia.com) Kristina Burström (kristina.burstrom@ki.se) Version: 3 Date: 17 January 2013 Author's response to reviews: see over
Reponses to reviewers comments and editorial requirements We would like to thank both reviewers for giving such detailed and constructive comments. Changes in the manuscript have been marked with blue text. Reviewer 1 The paper defines the research questions clearly and the methods are appropriate. However, the interpretation of the results is too general and at times not accurately stated. Major Compulsory Revisions: 1. Abstract, Results: The statement of there was a drop in mean EQ-5D index and EQVAS, is not accurate since this is a cross-sectional study and not a longitudinal study. It is accurate to state that the EQ-5D scores were lower with longer duration of diabetes. You cannot infer longitudinal change over time from different patient samples acquired at different time points. The results section of the abstract has been reformulated as to avoid the misconception of this being a longitudinal study. The first two sentences now read: Individuals with diabetes reported lower HRQoL, with a significantly lower mean EQ VAS score in all cohorts of disease duration compared with control individuals for both men and women, and with a significantly lower EQ- 5D index for women, but not for men, 15 years (0.76, p=0.022) and 24 years (0.77, p=0.016) after diagnosis compared with corresponding control individuals. 2. Methods, first paragraph: Additional description and details on the DISS are required for the reader to understand how the patient sample was captured. For example, information is needed on whether the new diabetes patients are from all areas of Sweden or from select regions or hospitals. The reader should not be required to read the cited papers [27,28] to be able to understand the disease cohorts and whether they are representative of new diabetes patients in Sweden We have added more information on DISS and the population register in the first paragraph of the methods section as for the reader to better understand the study population. 3. Methods, last sentence in first paragraph: This sentence needs to be re-worked because it is not the research objective stated earlier. I understand why the choice of the 4 cohorts was made but it is not clearly stated here because you mention stage of disease complications which is not part of your research objective and not defined or described further in the methods or results. Perhaps you could state that the 4 cohorts were chosen to provide a range of disease duration for examining the effect on HRQoL. True, the sentence has been reformulated according to your suggestion and has been changed to: The choice of these four cohorts was based on time since diagnosis, connected to our hypotheses that different disease durations may have dissimilar effects on HRQoL. 1
4. Methods, second paragraph: Age is mentioned as a matching criterion but the reader does not know age at what time point. Please add a description of the time point for age; for example, age at diagnosis of diabetes or age at time of EQ-5D questionnaire. A description of age is provided as a footnote to Table 1 but it needs to be in the methods as well. Also, the difference in age between the 2008 cohort and the other cohorts needs to be explained. The matching of age has been thoroughly described (methods section, second paragraph, third and fourth sentence) combining suggestions from reviewers 1 and 2. The footnote to Table 1 has also been reformulated. 5. Results, Reported problems in EQ-5D dimensions: Please insert the table and/or figure that corresponds to these results. Table 2 has been inserted at the end of the first sentence. 6. Results, Reported EQ-5D dimensions, second paragraph: The second part of this sentence is confusing and should summarize the results for the diabetes cohorts only. It would be important to point out that for women with diabetes that the proportion with problems in self-care and pain/discomfort increased as diabetes duration increased. For men with diabetes, the proportion with problems in mobility and pain/discomfort increased as diabetes duration increased. The paragraph has been reformulated, separating the diabetes cohorts and the control individuals. However, we feel that it is important to also mention the control individuals as the patterns regarding prevalence of problems in the dimensions are similar. The paragraph now reads: In general, the combined prevalence of numeric moderate and severe problems increased in all five dimensions by disease duration for individuals with diabetes. However, significant differences between individuals with a disease duration of 15 or 24 years compared to those with a shorter duration, could only be seen for self-care and pain/discomfort among women and for mobility and pain/discomfort among men. Similar overall patterns were found for control individuals with significantly more problems with pain/discomfort among women and with mobility and pain/discomfort among men. 7. Results, EQ-5D index and EQ-VAS and Figures 1 and 2: The reporting of the results for the mean scores needs clarity and additional data (p-values and/or SD or 95% CI) for both the text and figures. The reader cannot judge whether the comparisons are significant without the specific p-values and a measure of variance. For Figures 1 and 2, scores comparing diabetes vs. control, the p-values can be added for women and men with a bracket showing each comparison. The p- value comparing across diabetes cohorts should be added to the figure legend. The current information in the figure legends is confusing and not clear. P-values have been added to both figures and figure legends have been expanded and now also include p-values. 2
Additionally, the results in this section are not clear since summary statements are made without attention to the comparisons being made. a. Statement comparing only women with diabetes in different cohorts needs to be restated providing the correct result for a cross-sectional study; mean EQ-5D index decreased with increasing duration. Also, the statistical significance for these results is needed because it does not appear to be significant; for women with diabetes: 0.84, 0.84, 0.76, 0.77 and for control women: 0.90, 0.87, 0.83, 0.83. We understand that the expression over time leads to a misconception but it was used since we felt that disease duration was not applicable for the control individuals. However, we have changed this sentence as to avoid misunderstandings and it now reads: Comparison of women with diabetes in the different cohorts showed significant differences in mean EQ-5D index between the different cohorts of women with diabetes, which also applied for the control individuals. P- values have been added to the figure (comparison case-control) and figure legends (comparisons case-case and control-control) to show where significant differences could be found. b. Statement for men having the same pattern as women does not appear to be accurate for the comparison of diabetes vs. control for men. At 8 years duration the EQ-5D index was 0.87 vs. 0.88, at 15 years 0.85 vs. 0.85, and for 24 years 0.77 vs. 0.82. The statement should be re-worked to add clarity on what pattern (diabetes vs. control or across diabetes cohorts) is the same. The same has been changed to A similar and it has been specified that we mean comparisons between the groups of e.g. men with diabetes (third sentence). c. The statement of mean EQ-VAS was lower for individuals with the longest disease duration is not accurate for women (diabetes at 15 years was 71.9 and at 24 years was 73.4). We meant the two cohorts with the longest disease duration, but have reformulated the sentence to make it clearer: Mean EQ VAS scores were significantly lower for both women and men with diabetes compared with control individuals in all cohorts (Figure 2). 8. Results, Variation subsection: The second to last sentence is not clear. What is meant by disease-stratified models? Greater clarity/description of results is needed. We carried out regressions on the diabetes cohorts and control individuals separately to see if that changed the effect of the independent variables chosen. The analyses showed that women with diabetes had significantly lower health status than men with diabetes whereas the effect of disease duration was weaker and only significant 24 years after diagnosis. The effect of educational level was more pronounced among individuals with diabetes than control individuals. However, since we decided not to show the data, the paragraph describing the results has now been deleted. 9. Discussion: Overall, the summary of the key findings of the study is too general and does not accurately reflect the differences observed. Global statements are made which don t accurately state the findings based on sex or duration of diabetes. 3
The discussion has been rewritten to some extent according to suggestions below. See more detailed responses below. a. First sentence is not accurate as stated as 4 of the 5 dimensions. For men with diabetes, mobility and pain/discomfort (2 of the 5 dimensions) are more prevalent as duration of diabetes increased. For women with diabetes, self-care and pain/discomfort are more prevalent as duration increased. EQ-5D index did not decrease until 15 years for women and men with diabetes. EQ-VAS did not decrease until 15 years for women with diabetes and until 24 years for men with diabetes (no change from 1 year to 8 years for women and no change from 1 year to 15 years for men). True, the sentence was too generally written which made the statements incorrect. We have reformulated the first paragraph as a whole and it now reads: This study showed that selfreported mean EQ VAS score was significantly lower for individuals with diabetes for all cohorts of disease duration compared with matched control individuals. Mean EQ-5D index was significantly lower for women, but not for men, 15 and 24 years after diabetes diagnosis compared with corresponding female control individuals. One year after diagnosis, both women and men with diabetes reported significantly more problems in the dimension usual activities compared with corresponding control individuals. In the other dimensions, differences were found 15 and 24 years after diagnosis when comparing individuals with diabetes and control individuals. For women the differences were found in the dimensions mobility, self-care, usual activities and pain/discomfort and for men in mobility. b. First sentence of second paragraph: This sentence needs further clarity. Adding that this statement is for patients with 1 year duration compared with controls would make the statement more accurate. We have changed the sentence so that it is clear that we are talking about the newly diagnosed: To be diagnosed with diabetes is an upheaval in life that, for the newly diagnosed, affects the EQ-5D dimensions usual activities as well as mean EQ VAS score. c. Third sentence of second paragraph: This sentence contradicts the prior statements in this paragraph. Perhaps greater clarity would resolve this conflict; does reported HRQoL refer to EQ-5D index? Thank you! It should read EQ-5D index and not HRQoL. d. Third paragraph, second sentence: It is difficult to determine if this statement is accurate or an overstatement/generalization of the results. As the sentence indicates the comparison is between diabetes and control patients and the legend does not state any significant difference for women. P-values and measure of variance will help clarify this information. P-values have been added to the figures in order to support this statement. 4
e. Fourth paragraph: The statement for mobility affected by age and disease duration is not clear. The comparison should be across cohorts to address the impact of disease duration and only men had a significant association. The paragraph does not really add to the discussion and has therefore been removed. f. Fifth paragraph, last sentence: This sentence needs to be clarified; describe in greater detail what is meant by postponed negative effect on HRQoL. The sentence has been rewritten in order to clarify how changes in the management of diabetes have an impact on diabetes-related complications which in turn may have a negative effect on HRQoL: These changes in diabetes management likely contribute to reductions or postponements in diabetes-related complications, complications which may have a negative effect on HRQoL for individuals with diabetes. g. Sixth paragraph, last sentence: This sentence is not accurate and a common misconception. A cross-sectional study cannot provide information on how the disease affects HRQoL over time. A cross-sectional study such as this one can provide information on how the duration of disease impacts HRQoL. The cross-sectional study examines different patients from different cohorts who cannot be directly compared over time. The sentence has been rewritten and the reference to time deleted. It now reads: Studying four cohorts with different disease duration can, although not truly longitudinal, still give information on how the duration of diabetes impacts HRQoL beyond the effects of ageing. 10. Table 1: As mentioned above, the information in the footnote on age needs to be added to the Methods section and an explanation of why the other cohorts are age at 2007 and not 2009 needs to be added. Information about age has been added to the methods section, second paragraph, fourth sentence. The difference in year is due to that mean age was calculated the year the cohorts received the questionnaire which was 2007 for the 1983, 1992, and 1999 cohorts, and 2009 for the 2008 cohort. 11. Table 2, footnote: The explanation of the p-value for the comparison of individuals with diabetes and for the comparison of control individuals needs to be clarified and a different symbol used. It is confusing as written. The footnote has been changed in order to clarify which tests have been used for which p-value. 12. Figures 1 & 2: P-values need to be added by using a bracket to connote the comparison (diabetes vs. control) for each cohort and sex. The figure legends need to contain the actual p- value for the comparison across cohorts (within diabetes) for each sex. P-values have been added to the figure for case-control comparisons and to the legend for casecase and control-control comparisons. 5
Minor Essential Revisions: 13. Abstract, Results: It would be informative for readers to have the data reported in the results to support the statements. For example, the mean EQ-5D index and VAS, and % with problems in usual activities should be reported. Data has been added to the results section and general statements taken out in order to keep within the 350 words limit. 14. Background, first paragraph: Reference citations are needed for the first 2 statements. It would be helpful to provide references for mortality and morbidity for diabetes at younger ages as well as for the impact of hypoglycemia on health status. An article on the excess mortality in the incident cases in DISS have been added as well as two articles on the fear of hypoglycemia (ref 1-3). A recently published article by Gilet et al. (Demonstrating the burden of hypoglycemia on patients quality of life in diabetes clinical trials: measurement considerations for hypoglycemia, Value Health. 2012 Dec;15(8):1036-41) was found but not cited as only the abstract was available online at this time. The results, however, stated that objectively confirmed hypoglycemic events and HRQoL were not significant while patient-reported frequency of hypoglycemia and HRQoL were. 15. Results, Reported problems in EQ-5D dimensions: It is important to state the comparison being made for each statement, especially since the comparisons differ in this study (compare between diabetes and controls and compare across diabetes cohorts). For example, state that the comparison is with control women and control men for the statement of Fifteen years after diagnosis, women with diabetes reported more problems in the dimensions usual activities and pain/discomfort than control women, and men with diabetes in the dimension mobility AND PAIN/DISCOMFORT compared with control men. As noted here, pain/discomfort is significantly different for men but not mentioned in your results. In a wish to shorten the whole text, it has as you have pointed out, become unclear what statement is for what comparison. Regarding the dimension mobility, there is a significant difference between men with diabetes and control individuals. However, the results are reverse with the control individuals reporting more problems with mobility than men with diabetes. We have added a sentence including these results. The paragraph has been changed and now states: Compared with control individuals, both women and men with diabetes reported significantly more problems in the dimension usual activities 1 year after diagnosis (Table 2). Eight years after diagnosis, women with diabetes reported more problems in the dimension pain/discomfort than the control individuals. Fifteen years after diagnosis, women with diabetes reported more problems in the dimensions usual activities and pain/discomfort than their corresponding control individuals, and men with diabetes reported more problems in the dimension mobility than their corresponding control individuals. In the dimension pain/discomfort, men with diabetes reported less problems than corresponding control individuals. Twenty-four years after diagnosis, women 6
reported more problems in the dimensions mobility, self-care and usual activities than female control individuals. 16. Results, Variation subsection: The fact that 5 different models were used was not explained or described in the Methods section. It was a good exercise for the analysis to use the different models but the impact on the results for each incremental model is very slight and the results do not change significantly from one model to the next. There was only a slight drop in number of subjects included in the models and the R-square was best for model V. I recommend that this section and Table be condensed to provide the results of model V only in the table and text. A summary statement could be made in the text to indicate that the addition of each variable (education, marital status) did not significantly impact the final model. The first four models have been removed and the text rewritten to fit to the new table. The second and third sentences have been changed into: The model showed that sex, being diagnosed with diabetes, level of education and not being married or cohabiting all had significant negative impact on the health outcome measures along with disease duration of 8 years for EQ VAS score and disease duration of 15 and 24 years for both EQ-5D index and EQ VAS score. We also tested models adding the independent variables separately but that did not significantly impact the final model. 17. Discussion, last paragraph: The statement that the findings suggest that the performance of the Swedish diabetes care have improved is not supported or discussed. Recommend deleting this statement or adding more information that proves this statement. The sentence has been deleted. 18. Discussion, last paragraph: The term or concept of co-creation needs to be defined or discussed in further detail. It is unclear what is meant by this term. We have changed the sentence and now express it in terms of the patients being more active in their own treatment: An increased use of patient-reported outcome measures could emphasise the patient s perspective and increase the opportunities for patients to become more active in the management of their diabetes. 19. References: Several references do not have the year of publication listed; ref #6, #13, #20. Has been corrected. 20. Table 3: Recommend condensing this table to just Model V as noted above. The table has been condensed as recommended. 7
Reviewer 2 This study describes HRQOL among patients with diabetes. The paper is relatively well written and easy to understand with a clear conclusion. Still, there are potential for improvement: 1. It is unclear whether patients with type 2 diabetes were included All cases in the cohorts were included which means that a few are diagnosed with type 2 diabetes. The questionnaire does not have a question on which type of diabetes they have, but from the responses we know that 94% of responders are treated with insulin. We have added a sentence in the first paragraph of the methods section stating that all cases, regardless of type of diabetes, were included. 2. Were regression used to detect predictors of mean EQ5D index or simply EQ5D? I assume the latter was the case (see statistical analysis) In the background and the statistical analysis, we have clarified that the independent variables were chosen based on our literature search and hypothesis that these factors may have an impact on HRQoL. 3. How was age-matching performed: by year, five-year or? The matching of age has been thoroughly described combining suggestions from reviewers 1 and 2 (methods, second paragraph). The footnote to Table 1 has also been reformulated. 4. A justification for the covariates included in the regressions is lacking See answer to question 2. 5. The authors should avoid to make inferecnes of changing HRQOL over time because they use cross-sectional data. This means that the term difference between groups is better than change or reduction Changes have been made throughout the text in order to avoid references to time which could be misunderstood as longitudinal. 6. This reviewer consider that stepwise regression as presented in table 3 is theoretically incorrect. The authors should develop hypotheses about predictors of EQ5D index, test one models where all of the chosen covariates are included and then draw conclusions about the hypotheses. Based on this suggestion and a similar suggestion from reviewer 1, we have removed all models except the full model. Our hypothesis is more clearly stated (background, last paragraph) as is why these independent variables were chosen (statistical analysis, last paragraph). 8
Conclusion: The strengths of this paper lies in a clear patient population, straightforward method and clear results. The limitations lie in somewhat low response rate and inappropriate model testing. The latter limitations can easily be avoided. Additional editorial requirements: (1) Structure: Please include a?conclusion? section after?discussion?. A conclusion has been added after the discussion. (2) Competing interests: Manuscripts should include a?competing interests? section. This should be placed after the Conclusions/Abbreviations. If there are none to declare, please write 'The authors declare that they have no competing interests'. For more information please visit the instructions for authors on the journal website. We have added a section after the conclusion stating that we have no competing interest to declare has been added. We would be grateful if you could address the comments in a revised manuscript and provide a cover letter giving a point-by-point response to the concerns. All concerns have been responded to and changes in the text are marked in blue. Please also ensure that your revised manuscript conforms to the journal style (http://www.biomedcentral.com/info/ifora/medicine_journals ). It is important that your files are correctly formatted. We have gone through the instructions for authors again and trust that the files are now correctly formatted. 9