2025-00692. World Trade Center Health Program; Petitions 031, 036, 039, and 053-Amyotrophic Lateral Sclerosis; Finding of Insufficient Evidence

Aspect of associative causal inference (“Bradford Hill Criteria”) [Hill 1965]	Evaluation findings
Strength of association (and estimate precision)	Among six high-quality studies identified for evaluation, none examined ALS risk separately in 9/11-exposed populations [Colbeth et al. 2020, 2023; Jordan et al. 2011; Jordan et al. 2018; Li et al. 2023; Singh et al. 2023; Stein et al. 2016]. Among the six studies, only one reported a statistically significant positive association of indicating modest excess of mortality from nervous system disorders, including ALS, among WTC Health Registry community members [Jordan et al. 2018]. The authors attributed the observed excess to Alzheimer's disease, not ALS. The finding strongly depended on the choice of control group, indicating a potential for strong selection bias. The use of composite outcomes, external reference groups, and lack of exposure information are important study limitations common to all studies evaluated.
Consistency	All but the study by Jordan et al. [2018] reported less than expected deaths from nervous disorders when using an external reference population. Results supporting a causal association between 9/11 exposure and composite outcomes of neurologic diseases including ALS were not reproduced in different 9/11-exposed populations (e.g., firefighters, general responders, and community members). The lack of reproducible results is a strong limitation of causal inference.
Temporality	9/11 exposure was presumed to precede ALS onset because all studies were longitudinal and began observation on or after 9/11. However, no studies specifically examined temporal variations in risk.
Biological gradient	One study examined the exposure-response between categories of 9/11 exposure and mortality from a composite of other nervous system disorders (including ALS) in community members [Jordan et al. 2018]. That study found no evidence of increasing risk with 9/11 exposure.
Plausibility, Coherence, and Analogy	There are no established environmental factors that are causal for ALS; therefore, no 9/11 agent has been identified as a contributing cause. However, the literature supports a general conclusion that a causal association between a 9/11 agent (e.g., metals, silica, formaldehyde) and ALS is plausible, although unproven. The assumption that the risk observed in a composite outcome is analogous to ALS risk is unsubstantiated, which is an important study limitation.
Representativeness	There was representation of all groups of 9/11-exposed populations.