Methodologic considerations in trials assessing prevention of asthma exacerbation by vitamin D supplementation

Correspondence Methodologic considerations in trials assessing prevention of asthma exacerbation by vitamin D supplementation To the Editor: We read the article by Majak et al1 with great enthusiasm, especially because of their valuable efforts to verify new hypotheses. As we are planning to conduct a similar study in our hospital, this article was relevant to our objectives. There seemed to be a few methodological considerations in need of discussion by the authors; we want to mention them in no order of importance. Although ‘‘newly diagnosed asthma’’ is a clinically acceptable terminology, we expected the authors to mention asthma’s ‘‘severity’’ category, too; it is somehow obvious from the presented FEV1 scores or treatment dosages that possibly ‘‘mild-to-moderate’’ asthma has been considered. But in order for other researchers to be able to replicate the findings of this study, severity category and also the approach that the authors have taken for inclusion of such patients should be clearly stated. This generality was also true for ‘‘other chronic diseases’’ as exclusion criteria, because this entity was not clearly defined and the rationale for using it for exclusion was not well stated. Declaring and (the need for) controlling the effect of seasonal variation on asthma severity seems necessary in this ‘‘6-month trial,’’ something that may have an effect on main outcome measures in the mind of researchers.2 The odds ratio of 8.6 for the risk of asthma exacerbation with a wide CI from logistic regression analysis gives somehow unrealistic impressions for the effect of just one factor, namely, ‘‘decrease of 25(OH)D.’’ Newly published articles still show the complexity of the effects of vitamin D on the immune system and its potential role in asthma, regarding which the authors mention that the net effect of vitamin D on (and its role in) asthma is still waiting to be answered.3 We assumed that adjustments on age, sex, or any other factors relevant to asthma exacerbation could be reported (if any had been done), a fact that might change the calculated odds ratio and its CIs. Sample size justification needed more discussion; in a few backcalculations for determining the sample size for our own study,4 we used changes in ‘‘ATAQ score,’’ ‘‘FEV1,’’ ‘‘25(OH)D level,’’ and ‘‘the percentage of children who experienced asthma exacerbation’’ as parameters for choosing the right formula. The resulting sample size numbers differed substantially, and this gave rise to a feeling whether the power of this study (which used 48 participants) had been enough to examine robust changes. Lastly, the reporting style and the P values in Table II were suitable for ‘‘before-after’’ changes within groups, but because this was a parallel clinical trial, we expected to read the P values for ‘‘between-group’’ comparisons as it might have changed our impression of the effectiveness of vitamin D, not just the conventional kind of treatment that was the same in both intervention and control groups. Alireza Ahmadvand, MDa Behzad Darabi, MDb From aKnowledge Utilization Research Center and bChildren’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran. E-mail: ahmadvand.ar@ gmail.com.

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol 2011;127:1294-6. 2. Mohr LB, Luo S, Mathias E, Tobing R, Homan S, Sterling D. Influence of season and temperature on the relationship of elemental carbon air pollution to pediatric asthma emergency room visits. J Asthma 2008;45:936-43. 3. Mak G, Hanania NA. Vitamin D and asthma. Curr Opin Pulm Med 2011;17:1-5. 4. De Martini D. Conservative sample size estimation in nonparametrics. J Biopharm Stat 2011;21:24-41. Available online July 23, 2011. doi:10.1016/j.jaci.2011.06.032

Reply To the Editor: We are replying to the comments of Ahmadvand and Darabi1 regarding our article in the May 2011 issue of the Journal in which we described the clinical effect of vitamin D supplementation in asthmatic children.2 We aimed to verify the potentially favorable effect of vitamin D supplementation on newly diagnosed asthmatic children. Despite some methodologic limitations, we believe that our findings could be interesting for both clinicians and researchers. We are very glad to have the opportunity to answer these questions concerning our study. We find the reasons for doubts concerning the potential confounding of asthma severity and its seasonal variation on study end points as remote since the intervention took place in the same season for all the participants and clinical characteristics, including allergy profile, asthma symptoms score, and demographic, anthropometric, and lung function parameters, were all comparable between study groups at baseline. Indeed, our patients suffer from mild-to-moderate IgE-dependent asthma. All chronic diseases potentially related to the study end points and intervention have been defined as exclusions. Odds ratios for the risk of asthma exacerbation have been calculated for the visualization of main study findings, and we agree that such an approach in a relatively small sample could be controversial and the effect size of vitamin D supplementation in a large population could be lower. Nevertheless, the prevalence of asthma exacerbations in both groups is well visible in Fig 2 of article and the difference is still impressive. Between-group comparisons with P values obtained by using analysis of variance are shown in Fig 2. Table II of our original article shows withingroup comparisons as a result of not only additional but also clinically important analysis. Obviously, both analyses allow for distinct conclusions. Finally, sample size is a matter of concern. The study was designed to have 95% power (for 20 completing patients per treatment arm) to detect a difference of 20% in 25(OH)D between groups on the assumption that variability was similar to that observed in the previous study. An allowance was made for 20% dropout rate. This estimation was explained by the additional aim of the study—the effect of inhaled corticosteroids and vitamin D3 on bone metabolism.3 Since such an approach could leave the study underpowered for conclusions on changes in prevalence 1131