In Chapter 2, the committee critically evaluated the available literature on the potential association between service in the military and development of amyotrophic lateral sclerosis (ALS). The committee then presented its conclusion based on the evidence derived from the published studies. The committee concluded that there is limited and suggestive evidence of an association between military service and development of ALS. In this chapter, the committee lays out specific recommendations to assist the Department of Veterans Affairs (VA) in gathering more information on ALS in the veteran population so that VA might be able to determine more definitively whether there is an association. The committee also provides guidance for studying ALS risk factors that are potentially relevant to military service.
RECOMMENDATION 1: USE DATA FROM OTHER EPIDEMIOLOGIC STUDIES
Despite the importance of clarifying the relationship between military service and the subsequent risk of ALS, and the challenges faced in drawing a conclusion about it, it is unlikely that prospective cohort studies will be designed de novo to examine this question. For this reason, the committee recommends that existing cohort studies designed for other outcomes be explored for their suitability to assess the relationship between ALS and military service. The study by Weisskopf et al. (2005), which used a cohort assembled for purposes other than studying ALS, provided evidence of an association despite limitations inherent in the conduct of secondary analyses (for example, the lack of information on some important variables related to ALS, the use of self-report of military service, and the identification of ALS through death certificates as a proxy for ALS incidence). Cohorts assembled outside the United States (for example, in Canada and
the United Kingdom and other European countries) should also be considered.
Cohort studies of sufficient size and length of follow-up in which information on military service was collected for all subjects, or can be collected retrospectively in a valid manner from records or from the subjects themselves, may prove useful in examining the relationship between ALS and military service. In some studies, it may be convenient to design a case-control study nested within the cohort to reduce the cost of additional data collection about military exposures. The advantage of traditional cohort studies or nested case-control studies is that they provide a well-defined base population (although not necessarily representative of the general population), and information for a number of potential confounding variables has been collected prior to disease occurrence, thus avoiding recall bias. A cohort would be especially valuable if subjects had provided extensive details about their military experience. Ideally, “exposure” information should include
Whether a person served in the military.
Location of military service.
Years of military service.
Jobs and duties during military service.
The opportunity to validate military service using historical documents would further add to the methodologic rigor of such a study. Linkage with death certificates or other mechanisms for monitoring the occurrence of ALS would be necessary. Prospective monitoring of the cohort for ALS incidence that allows for application of the modified El Escorial diagnostic criteria would be ideal because it would reduce underascertainment and misclassification of disease. However, that may not be feasible. Alternatively, if death certificates are the only source of information on ALS, the investigators should consider validating a subset of diagnoses to estimate the frequency of false positives and false negatives.
High quality case-control studies could also be used to assess the relationship between ALS and military service.
Ongoing or completed rigorous case-control studies of ALS that pay close attention to reducing sources of bias and that collected details about military service as outlined above would be suitable. Case-control studies may permit a tighter control for putative confounding variables, such as lifetime occupational history and trauma, which are not regularly collected in cohort studies designed to assess other outcomes. In addition, in case-control studies, it is easier to attain a more rigorous case definition applying modified El Escorial diagnostic criteria and to ensure the exclusion of motor neuron disease other than ALS (such as primary lateral sclerosis).
In summary, for any secondary analysis of military service and ALS, in even the most rigorously designed and conducted epidemiological study, it is important to carefully assess the quality of the exposure and outcome data that have been collected and the adequacy of the sample size for drawing conclusions.
The National Registry of Veterans with ALS (Kasarkis et al. 2004), although important, is inappropriate to serve as the basis for a cohort study or a case-control study because it is limited to cases of ALS, and the selection of an appropriate comparison (control) group would be difficult because the base population from which cases were identified is not clearly defined.
RECOMMENDATION 2: IN-DEPTH ANALYSIS OF EXISTING RISK-FACTOR STUDIES
In addition to reviewing the literature on military service and the development of ALS, the committee reviewed selected published studies that examined the role of a number of putative risk factors in the etiology of ALS and identified several factors that may be important in relation to military service (see Box 3.1). Those risk factors might be confounding variables in the relationship between military service and ALS, and military service itself might be a proxy for any of those variables. Appendix A contains brief summaries of the putative risk factors listed in Box 3.1; its purpose is to highlight key studies on the risk factors, but it is not a comprehensive review or critique. Appendix B illustrates three possible conceptual models for linking military service and other risk factors with ALS; the models are provided as
aids for visualizing the complexity of the possible mechanisms and are not intended to be exhaustive.
It is beyond the scope of the committee’s work to conduct in-depth systematic reviews of the literature to gauge the potential importance of risk factors, and the committee does not suggest that the risk factors reviewed in Appendix A constitute a complete list of military-service-associated potential risk factors for ALS. The committee recommends that VA identify putative risk factors relevant to military service, particularly risk factors common to military service since the 1940s, and conduct in-depth systematic literature reviews on them.
Putative ALS RiskFactors Relevant to Military Service
RECOMMENDATION 3: CONDUCT ADDITIONAL EPIDEMIOLOGIC STUDIES OF THE ASSOCIATION BETWEEN MILITARY SERVICE AND AMYOTROPHIC LATERAL SCLEROSIS
In reaching the conclusion of limited and suggestive evidence of an association between military service and later development of ALS, the committee was hampered by the paucity of well-conducted epidemiologic studies that are sufficiently free of bias. In particular, few studies were designed to be able to consider the possible confounding effects of other risk factors for ALS. The committee therefore recommends that further corroborative and exploratory studies be designed and conducted to elucidate the relationship between military service and ALS. Particular attention should be paid to the inclusion of risk factors
that might be related to the development of ALS and to their adequate measurement (or methods of accounting for them in study design). The results of the systematic literature reviews described in Recommendation 2 should provide information to help researchers to design the further studies.
Kasarkis EJ, Dominic K, Oddone EZ. 2004. The National Registry of Veterans with Amyotrophic Lateral Sclerosis: Department of Veterans Affairs Cooperative Studies Program (CSP) #500a. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 5(Suppl 1):129–132.
Weisskopf MG, O’Reilly EJ, McCullough ML, Calle EE, Thun MJ, Cudkowicz M, Ascherio A. 2005. Prospective study of military service and mortality from ALS. Neurology 64(1):32–37.