Author s response to reviews Title: Prevalence and incidence of multiple sclerosis in central Poland, 2010-2014 Authors: Waldemar Brola (wbrola@wp.pl) Piotr Sobolewski (piotrsobolewski@poczta.onet.pl) Stanisław Flaga (stanislaw.flaga@agh.edu.pl) Małgorzata Fudala (malgorzatafudala@poczta.onet.pl) Wiktor Szczuchniak (wikopat2@wp.pl) Jan Stoiński (jstoinski@go2.pl) Anita Rosołowska (rosanita100@wp.pl) Jacek Wójcik (jmwojcik@esculap.pl) Katarzyna Kapica-Topczewska (katarzyna-kapica@wp.pl) Danuta Ryglewicz (ryglew@ipin.edu.pl) Version: 1 Date: 25 Mar 2016 Author s response to reviews: The Editor BMC Neurology 25 March 2016 Dear Editors and Reviewers, We would like to express our sincere gratitude to the reviewers for their time and effort in reviewing our manuscript, Prevalence and incidence of multiple sclerosis in central Poland, 2010-2014. The reviewers have offered many thoughtful comments. We found all the suggestions immensely helpful, and we believe they have helped us to significantly improve our manuscript. Added text is highlighted in the paper. Point-by-point responses are detailed below.
We hope that the editors and reviewers find our changes sufficient and deem our manuscript worthy of publication in BMC Neurology. We look forward to hearing from you at your earliest convenience. Yours sincerely Waldemar Brola, on behalf of all co-authors Department of Neurology Specialist Hospital in Końskie 41 Gimnazjalna Street 26-200 Końskie Poland E-mail: wbrola@wp.pl Tel.+48601314415 Fax +48413902364 Reviewer #1: We would like to thank for valuable remarks and constructive comments, which significantly helped us to improve our manuscript. Below we present point-by-point responses to the comments. In this study, the authors described prevalence and incidence of MS in the Swietokrzyskie Region (central Poland). They found that levels of both incidence and prevalence in the Swietokrzyskie region confirm that the central Poland is a high risk area for MS. They also registered that the prevalence of MS has increased during recent years. The question of the study is clearly defined. However, there are many mistakes regarding terminology. For example, cross-sectional study IS NOT longitudinal study; authors stated that this study is cross-sectional and longitudinal study. Exactly, it is typical descriptive epidemiological study performed with aim to estimate frequency and distribution of the disease in defined population. Author s reply: We completely agree with the reviewer. The incorrect term has been removed from the manuscript. Another important mistake is made in terms of precise definition of prevalence and incidence. Prevalence is not rate, it is a proportion (number of all cases in point of measurement divided by population at the same time point). Incidence is rate with numerator (number of new cases in defined point of time) divided by person-years at risk. Therefore, authors should clearly state precise period in which incidence was measured.
Author s reply: The definitions of Prevalence and Incidence are included in the Materials and methods section. Prevalence rate in Table 2 and in the whole manuscript was replaced with Prevalence. The period of time during which "Incidence" was assessed has been defined more precisely. The following paragraph was added to the Statistical analysis section: Prevalence was expressed as the number of all cases on the prevalence day divided by the population of the Swietokrzyskie Voivodeship on the same day (available in the Demographic Yearbook of Poland 2015) [14]. Crude sex and age area-specific prevalences were calculated as the number of cases on prevalence day per 100,000 inhabitants. The prevalence of MS was adjusted by a direct method, using the Polish and European population as a standard [17]. The incidence was calculated annually (on 31st December) using the number of newly diagnosed cases each year from 1st January to 31st December as the numerator and the size of the population as per the official data every year from 2010 to 2014, according to the Polish Central Statistical Office. The mean incidence was then calculated as a mean of the individual yearly values in the 5-year period. Additionally, the manuscript adheres to the relevant standards for reporting and data deposition. Tables and figure are informative and concisely described in the section Results. Data analysis is performed by using adequate statistical methods, except analysis of incidence trends. Firstly, it is very short time period for analysis of time series, but besides that it is not clearly presented how they obtained significance of time trend in men and women. Author s reply: We agree with the reviewer's suggestion that the 5-year observation was too brief for analysis of time series, especially as the incidence rate in 2015 (time period not included in our research) was lower than in previous years. Following advice of our consulting neuroepidemiologist, we decided to refrain from analysis of incidence trends and wait for further development of the register (for the next 5 years). Thus, we removed a paragraph concerning incidence trends from the Results section, providing only mean incidence rates for men and women over the 5-year period, and added further discussion on this issue in the Discussion section. Minor points include typing errors (page 6, 140th line: please check prevalence day!) and reference list mistakes (all references should be cited according to recommendations of the BMC Neurol, especially ref. 4 and 7). Author s reply: The error in the line 140 was corrected prevalence day (December 31, 2014). The reference list was reviewed and corrected in accordance to recommendations of the BMC Neurol. Keeping in mind that one of the most interesting findings in this study is related to calculation of MS incidence, the authors should discuss it more comprehensive including all challenges in its
precise estimation. Other parts of the discussion are adequately supported by the data. The limitations of the study are stated. Author s reply: The discussion concerning MS incidence was expanded with additional focus on obstacles and difficulties in defining precise incidence rates, as well as describing upward trends that can be observed in the recent years. The following paragraph was added to the Discussion section: In our study, the mean incidence rate was 4.2 per 100,000/year. Between 2010 and 2014, a gradual increase in incidence among women (3,5/100,000/year in the first year of the study [2010] to 8.2 in the last year of observation [2014]) was observed. Such a trend was not observed in men (no significant increase from 2.3 to 3.1). However, the time of observation was too short for a thorough analysis of the trend in incidence, and the reasons behind any increase. Our registry started functioning in 2010, and an increase in incidence rates could be related to constantly improving methods of gathering and analysis of data, as well as greater involvement of the facilities included in our research. We anticipate that RejSM will continue to develop through the coming years, which will allow long-term observation of MS patients and more detailed analysis, as well as more precise estimation of prevalence and incidence. In conclusion, this study offers some findings, but methodological issues have to be improved. Authors are advised to consult neuroepidemiologist for help in resolving these issues. Author s reply: We hope that the changes mentioned above have contributed to improvement of methodological quality. We would also like to thank you for suggesting we discuss our results with a neuroepidemiologist. We hope that the advice of Prof. Andrzej Potemkowski, Polish author of numerous articles in the field of neuroepidemiology, has contributed to an improvement in the methodological quality of our research. Thanks to Prof. Potemkowski was added to the Acknowledgements section. As suggested by editor from Edanz Group, we changed title of articles: Prevalence and incidence of multiple sclerosis in central Poland, 2010-2014. Reviewer #2: We sincerely thank the Reviewer for the thorough reading of our manuscript and the helpful comments. We have revised the manuscript according to the recommendations. It is of interest to study both the incidence and the prevalence of MS in Poland. This study aims at giving data for a defined geographical region based on a national registry. As far as one can understand the patients were recruited based on contact with neurologists with special interest in MS over a period of 5 years. One would assume that a proportion of patients with MS, especially
patients with long-standing disease, might not have seen a neurologist during this period. Thus the figures are most probably an underestimation, and this seems to be the case as the mean age of 43 years seems low, the proportion of patients older than 54 years is low and the proportion of patients with SP disease is lower than expected. Author s reply: We agree with the comments. The number of elderly patients with long-term disease, especially secondary progressive MS patients, may be underestimated. Difficulties in reaching people who rarely have contact with medical services or who attend their GP rather than a neurologist may result in omission from the registry, which is an issue for all epidemiological registries. Long-term observation and an aim for complete identification of all patients is desirable for accurate estimation of prevalence and incidence. The above discussion was added to the paragraph on study limitations. It is stated that the rates are adjusted to the European Standard Population, but neither table 2 nor 3 gives any figures. This should be included, as well as the appropriate reference. Author s reply: Age-adjusted prevalence and incidence for the European Standard Population were added below Table 2 and 3. References were updated to include literature concerning the European Standard Population. Pace, M, Lanzieri G, Glickman M, Zupanic T. Revision of the European Standard Population: Report of Eurostat's Task Force. Eurostat: methodologies and working papers. Brussels: Publications Office of the European Union; 2013. The following paragraph was added to the Results section: The crude annual incidence of MS in this population was 4.2 (95% CI, 3.7 4.4) per 100,000 per year over the 5-year period (5.9 for women and 2.5 for men), and age-standardized rates (adjustment to the European population) of 4.12 [3.32-5.14], 5.68 [4.45-7.82], and 2.21 [1.12-3.31], respectively. Additional comments: -Is this really a longitudinal study? No, it is a case collection with case ascertainment over a period of 5 years. Author s reply: This was a epidemiological study, not a longitudinal study. The statement in the manuscript was corrected. - Regarding age at onset and diagnosis range should also be given.
-Time from onset to diagnosis is of interest as the incidence figures for the latest period is expected to be lower depending on the mean time from onset to diagnosis (median and range will also add important information). Author s reply: In Table 1, range was added to the variables describing age at disease onset and age at diagnosis, and median and range were added to mean time from onset to diagnosis. The following was added to the Results section: The mean length of time between onset of the first symptoms and diagnosis was 28.8±56.2 months, with a median of 22 months (range, 1 168 months). The article needs some language corrections before being published. Author s reply: The revised manuscript has been edited by a native-english-speaking academic editor from Edanz Group. As suggested by editor from Edanz Group, we changed title of articles: Prevalence and incidence of multiple sclerosis in central Poland, 2010-2014. Reviewer #3: Accepted. The manuscript provides new information about incidence and prevalence rate of MS in Poland. Another important information is the data archived in an electronic register. The levels of incidence and prevalence rate in Central Poland is higher than previous studies, possibly due to the fact that the collection of data was performed by experienced neurologists, introduction of routine MRI examination, early diagnosis and treatment with an intense search for cases. Probably, the newest and the oldest cases may not have been identified. Perhaps, it should be taken into account diagnostic error in some cases. We would like to thank Reviewer #3 for the positive feedback.