Response to Belli and Vanacore

Response to Belli and Vanacore

Letters to the Editor Sports and amyotrophic lateral sclerosis Dear Sir, We read with interest the paper by Carmel Armon published in the last issue...

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Letters to the Editor

Sports and amyotrophic lateral sclerosis

Dear Sir, We read with interest the paper by Carmel Armon published in the last issue of the Journal [1], which raises a number of substantial questions and solicits deeper insight in the association between ALS and some sports, namely soccer. Since in this context some criticism was formulated to our proportionate mortality analysis of Italian soccer players [2], we would like to provide the following additional comments. In the results section Armon states that our study, like a few others, is based on the comparison of patients with ALS to a reference group. While this definition can be applied to casecontrol studies, evidently it does not fit to the cohort study design that we adopted. Armon expresses some concern because our study was published in 2004 but mention of it had been made in 2003, in a comment by Beretta et al published in Lancet Neurology [3]. The reason for this delay is that we performed the study acting as court's experts, and we were authorized to publish it in a scientific journal subsequently to its uncovering in the legal setting. Armon suggests that our study suffers from a critical methodological shortcoming with respect to the computation of the expected number of cases in the PMR analysis. We reject this criticism for two reasons. Firstly, we followed the procedure that is described in the international scientific literature [4,5] and that is referred to by the authors of validated software commonly used by epidemiologists [6,7,8]. Secondly, the alternative method suggested by Armon (that so far – to our knowledge – has not been endorsed in the epidemiological literature) does not imply proper age — standardization, but introduces a number of steps characterized by a sequence of not fully verifiable assumptions whose rationale is not clearly stated. Furthermore it is not readily understandable why the conventional contrast between observed and expected cases in proportionate mortality studies should be regarded as a comparison between apples and oranges. The latter notion, however, is seldom, if ever, encountered in peer-reviewed journals. With regard to the issue of the healthy worker effect, we stated that the scientific literature supports its role on cardiovascular and respiratory mortality, but there are no suggestions (that is, no reviews, consensus reports or well assessed evaluations) for its role on neurological disorders. The suggestion to systematically review and evaluate ALS mortality in occupational cohort studies is valid and we fully endorse it. In the light of the aforementioned points, we recommend that the issue of a possible association between soccer and ALS, especially in the bulbar form, be the object of further scientific research.

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References [1] Armon C. Sports and trauma in amyotrophic lateral sclerosis revisited. J Neurol Sci 2007;262:45–53. [2] Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease? Eur J Epidemiol 2005;20:237–42. [3] Beretta S, Carri MT, Beghi E, Chio A, Ferrarese C. The sinister side of Italian soccer. Lancet Neurol 2003;2:656–7. [4] Rothman KJ, Greenland S. Modern Epidemiology. Philadelphia, PA: Lippincott-Raven Publishers; 1998. [5] Checkoway H, Pearce N, Crawford-Brown DJ. Research methods in occupational epidemiology. New York Oxford: Oxford University Press; 1989. [6] Marsh GM, Preininger M. OCMAP: a user-oriented occupational cohort analysis program. Am Stat 1980;34:245–6. [7] Marsh GM, Ehland JJ, Paik M, et al. OCMAP/PC: a user-oriented occupational cohort mortality analysis program for the IBM/PC. Am Stat 1986;40:308–9. [8] Marsh GM, Co-Chien HT, Rao BR, Preininger ME, Ehland JJ. OCMAP: module 6 extended proportional mortality analysis with simultaneous inferential procedures. Am Stat 1989;46:127–8.

Stefano Belli Nicola Vanacore* National Institute of Health, Viale Regina Elena 299, 00161 Roma, Italy ⁎ Corresponding author. E-mail address: [email protected] (N. Vanacore). 31 October 2007

doi:10.1016/j.jns.2007.12.020

Response to Belli and Vanacore I appreciate the comments of Drs. Belli and Vanacore on my recent article [1], and the opportunity to discuss them. They ask why I disputed the results of the accepted methodologic procedure that they followed in their paper. There are two reasons. First — as discussed in a paper I published in 1991 [2], I am inclined to suspect any calculation that results in an expected number of cases of ALS of 1 or less in a given cohort or population, and then makes a claim of excess based on identification of a small number of cases. Second — there appeared to be an inconsistency between the results of calculations of expected cases performed by Belli and Vanacore – 0.69 expected cases in 24000 soccer players [3] – and the results of Chio et al. – 0.77 expected cases in 7325 soccer players [4]. An additional paper published since by Taioli [5] adds to this perception of inconsistency, when she calculates only 0.2 expected cases in a cohort of 5389 soccer players. None of these authors discussed these inconsistencies, or considered the possibility that an estimate of less than 1 expected case of ALS might be incorrect. I preferred originally not to elaborate why use of these methods of calculating expected numbers of

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Letters to the Editor

cases of ALS may result in incorrect estimates in this instance. However, several possibilities come to mind. First is the issue that the base rates in the reference population, at times resulting from populations in whom case finding is less complete than in the target population, may be too low. Second is the possibility that rates may increase over time. Third is the possibility that the method, while reliable when the expected rates are high, may become less accurate when the expected rates are low. Fourth, an elaboration on the third, is that the calculation of confidence intervals when using this method considers the magnitude of possible error only in the numerator, but not in the denominator. There is no formal accounting for the possibility that there may be an error in the point estimate itself. In general, the proportionate error of a ratio is the sum of the proportionate errors of numerator and denominator. Failure to account for the error in the denominator underestimates the magnitude of possible error in the ratio. When the estimate is close to zero, the relative magnitude of the error becomes very large. This list is not exhaustive. Rather than going down this route, I found it simpler to use an alternative method to calculate the expected number of cases. The alternative approach resulted in a much larger number of expected cases: this underscored the fact that the other estimates were too low. Drs. Belli and Vanacore criticized in broad terms the alternative method I proposed and stated that it had not been endorsed in the epidemiologic literature. In general, this might be viewed as a legitimate concern. Checking some of the classical epidemiologic texts, I was not able to find this method described; nevertheless, I doubt that I can claim to have developed it. I was gratified that Chiò et al. [6] followed it easily, and suggested only one specific modification to the calculation, not questioning the method itself, or other elements of the calculation. Some rationale for this method is provided in the original paper [1]. Additional discussion of the implications of some of the assumptions may be found in my response to Chiò et al. [7], where I discuss how the first pass approach may be refined. Thus, unless the critiques with regards to the method I proposed can be more specific, these general concerns should be set aside. Drs. Belli and Vanacore request that I clarify my use of the “apple and oranges” figure of speech. The “apples” refer to an expected number derived from general mortality data, where there is reason to suspect that ALS is under-identified and under-reported. The “oranges” refer to an observed number in a special population, such as soccer players, where a special effort has been made to identify all cases, and the reporting of ALS on death certificates is likely to be more complete. Further discussion may be found elsewhere [8]. I stand by my expression of concern, when the publication of the results [3] lags their public disclosure by 2 years. This delay results in general acceptance of the original announcement because, lacking data, there is no factual basis to question it. By the time data become available so the original conclusions can be questioned, there is little opportunity to change what has become accepted as established fact. If any discussion takes place, it is confined to limited professional circles, and has little

perceived impact beyond those circles. I hope that the present dialogue will prompt the judicial system under which Drs. Belli and Vanacore work to find ways to permit peer review of experts' analyses prior to their presentation in court and their acceptance as indisputable facts. Drs. Belli and Vanacore may elect to share this correspondence with the court in question. Drs. Belli and Vanacore are concerned with my use of the term “reference group” to refer to an entire population. I do not understand the basis for this concern, or see how it has bearing on the substantive discussion. There are two points on which Belli, Vanacore and I are in agreement. First, we agree that there are no assessments of the possible role of the healthy worker effect on neurological disorders. Second, we agree that if there is excess bulbar ALS in Italian soccer players it should prompt further study. However, we differ on what it is that needs to be studied further. As discussed in the original article [1] and in a previous response [7], I view the identification of bulbar onset ALS in Italian soccer players, who became the focus of interest because of a report of “diffusion of illegal drugs” among them, as requiring further investigation among current and future affected Italian soccer players aimed to identify what they may have ingested. These reports do not serve as a basis for extrapolating the possible findings to all soccer players. I thank Drs. Belli and Vanacore for the opportunity to discuss these points. References [1] Armon C. Sports and trauma in amyotrophic lateral sclerosis revisited. J Neurol Sci 2007;262:45–53. [2] Armon C, Daube JR, O'Brien PC, Kurland LT, Mulder DW. When is an apparent excess of neurologic cases epidemiologically significant? Neurology 1991;41:1713–8. [3] Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophio lateral sclerosis an occupational disease? Eur J Epidemiol 2005;20:237–42. [4] Chiò A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among professional football players. Brain 2005;128:472–6. [5] Taioli E. All causes mortality in male professional soccer players. Eur J Public Health April 12 2007:1–5 [Electronic publication]. [6] Chiò A, Traynor BJ, Swingler R, Mitchell D, Hardiman O, Mora G, et al. Amyotrophic lateral sclerosis and soccer: a different approach strengthens the previous findings. (Letter to the editor). J Neurol Sci 2008. [7] Armon C. Response to Chiò et al. J Neurol Sci 2008. [8] Armon C. An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis. Neuroepidemiology 2003;22:217–28.

Carmel Armon Division of Neurology, Baystate Medical Center S4648, 759 Chestnut Street, Springfield, MA 01199, United States Tel.: +1 413 794 4754. E-mail address: [email protected].

doi:10.1016/j.jns.2007.12.025