Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis survival

<div><p>Background</p><p>Military veterans may have higher rates of amyotrophic lateral sclerosis (ALS) mortality than non-veterans. Few studies, with sparse exposure information and mixed results, have studied relationships between military-related factors and ALS survival. We evaluated associations between military-related factors and ALS survival among U.S. military veteran cases.</p><p>Methods</p><p>We followed 616 medical record-confirmed cases from enrollment (2005–2010) in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study until death or July 25, 2013, whichever came first. We ascertained vital status information from several sources within the Department of Veterans Affairs. We obtained information regarding military service, deployments, and 39 related exposures via standardized telephone interviews. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals. We adjusted for potential confounding and missing covariate data biases via inverse probability weights. We also used inverse probability weights to adjust for potential selection bias among a case group that included a disproportionate number of long-term survivors at enrollment.</p><p>Results</p><p>We observed 446 deaths during 24,267 person-months of follow-up (median follow-up: 28 months). Survival was shorter for cases who served before 1950, were deployed to World War II, or mixed and applied burning agents, with HRs between 1.58 and 2.57. Longer survival was associated with exposure to: paint, solvents, or petrochemical substances; local food not provided by the Armed Forces; or burning agents or Agent Orange in the field with HRs between 0.56 and 0.73.</p><p>Conclusions</p><p>Although most military-related factors were not associated with survival, associations we observed with shorter survival are potentially important because of the large number of military veterans.</p></div

Military deployments or danger pay and amyotrophic lateral sclerosis survival in GENEVA^a, United States of America, 2005–2013.

<p>Military deployments or danger pay and amyotrophic lateral sclerosis survival in GENEVA<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185751#t004fn002" target="_blank">^a</a>, United States of America, 2005–2013.</p

Military service and amyotrophic lateral sclerosis survival in GENEVA^a, United States of America, 2005–2013.

<p>Military service and amyotrophic lateral sclerosis survival in GENEVA<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185751#t003fn002" target="_blank">^a</a>, United States of America, 2005–2013.</p

Military exposures and amyotrophic lateral sclerosis survival in GENEVA^a, United States of America, 2005–2013.

<p>Military exposures and amyotrophic lateral sclerosis survival in GENEVA<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185751#t005fn002" target="_blank">^a</a>, United States of America, 2005–2013.</p

Demographic characteristics of amyotrophic lateral sclerosis deaths and total cases^a in GENEVA, United States of America, 2005–2013.

<p>Demographic characteristics of amyotrophic lateral sclerosis deaths and total cases<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185751#t001fn002" target="_blank">^a</a> in GENEVA, United States of America, 2005–2013.</p

Flow chart showing the ascertainment of GENEVA cases, United States of America, 2005–2010.

<p>Solid boxes or lines depict cases who progressed past each step shown. Small-dashed boxes or lines depict cases who did not progress past each step shown, but who were incorporated into the analysis indirectly via inverse probability weights (see Statistical Analyses and Section C in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0185751#pone.0185751.s001" target="_blank">S1 File</a> for more details). Among the 27 cases ineligible for GENEVA, reasons included dementia (n = 9), diagnosis change (n = 4), withdrawal from the Registry DNA bank (n = 3), or interview infeasibility (n = 11). Abbreviations: ALS, amyotrophic lateral sclerosis; GENEVA, Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study; PLS, primary lateral sclerosis.</p

Adjusted odds ratios for the associations between mean DMR methylation for <i>PEG3</i>, HPV status and CIN and ICC.

*<p>Controlling for HIV-1 status, HPV positive status, age, and oral contraceptive (OC) use.</p><p>Per 5% methylation increase.</p

Distribution of participant characteristics by case-control status.

*<p>ICC/Cancer subtype: 45 patients had squamous cell carcinoma; 3 had adenosquamous carcinomas.</p><p>High Risk HPV- 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68.</p><p>Low/Other Risk HPV – 6,11, 26, 40, 42, 55, 61, 62, 69, 70, 72, 73, 81, 82, 83, 84.</p

Validation of the <i>PEG3</i> pyrosequencing assay.

<p>Defined mixtures (x-axis) of methylated and unmethylated DNAs were prepared and analyzed in quintuplicate by pyrosequencing (y-axis). The results shown represent the mean; error bars indicate standard deviations. The Pearson rho is 0.953 with a p-value of 0.004.</p

Correlation between High and Low Risk HPV status and methylation fraction means at differentially methylated region (DMRs) of <i>PEG3</i>.

<p>High Risk HPV - 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68.</p><p>Low/Other Risk HPV – 6, 11, 26,40, 42, 55, 61, 62, 69, 70, 72, 73, 81, 82, 83, 84.</p