Trauma and amyotrophic lateral sclerosis: a case–control study from a population‐based registry

May combine two claims.

Significant differences were found between cases and controls for injuries to the arm, head, abdomen, and spine.

“Significant differences were found between cases and controls, in decreasing order, for arm, head, abdomen, and spine.”

May combine two claims.

Cases reported more injuries than both control groups, and this was confirmed after excluding events that occurred within 5 years from symptom onset.

“However, cases reported more injuries than both control groups.This was confirmed after excluding events that had occurred within 5 years from symptom onset.”

May combine two claims.

The association between trauma and ALS remained significant when the analysis was limited to events occurring 5+ and 10+ years before ALS onset, to incident ALS, and to direct informant.

“The ORs remained significant when the analysis was limited to events occurred 5+ and 10+ years before ALS onset, to incident ALS, and direct informant.”

May combine two claims.

Amongst patients with old traumatic events, the risk was largely limited to men and patients with limb-onset ALS.

“Amongst patients with old traumatic events, the risk was largely limited to men and patients with limb-onset ALS (Table 4).”

May combine two claims.

Significance was retained for history of at least one traumatic event, 3+ events, moderate or severe events, and 2+ events requiring hospitalization or leading to disability when multivariate analysis was limited to incident ALS, direct informant, and very old traumatic events.

“Significance was retained for history of at least one traumatic event, 3+ events, moderate or severe events, and 2+ events requiring hospitalization or leading to disability when multivariate analysis was limited to incident ALS, direct informant (excluding surrogate), and very old traumatic events (see online only Table S1).”

May combine two claims.

Cases reported more severe traumatic events, more events requiring hospital admission, and more events followed by disability than controls.

“Cases also reported more severe traumatic events than controls, and more events requiring hospital admission or followed by disability.”

May combine two claims.

Fractures, contusions, and concussions each predominated in patients with ALS.

“Fractures were the commonest injury, followed by contusions and concussions.Each of these injuries predominated in patients with ALS.”

May combine two claims.

The association between trauma and ALS was strengthened after multivariate analysis, and all ORs were significant.

“The association between trauma and ALS was strengthened after multivariate analysis (Table 3).All ORs were significant.”

May combine two claims.

In our sample, men reported more traumatic events than women (65.8% vs 50.0% for at least one event; 54.6% vs 32.2% for events 5+ years before symptom onset).

“In our sample, 152 men (65.8%) and 73 women (50.0%) reported at least one traumatic event; the figures were 126 (54.6%) and 47 (32.2%)only for traumatic events dating back 5 years before the symptom onset.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

2.0% of controls and 5.3% of cases reported 2+ traumatic events followed by hospital admission, figures comparable to those expected from the power calculations.

“In addition, 2.0 and 5.3% of controls and cases, respectively, reported 2+ traumatic events followed by hospital admission (see Table 2), figures comparable to those expected from the power calculations.”

Probably not a substantial claim: may not pass S3 (load-bearing).

An association between a history of head trauma and ALS was found by several others.

“An association between a history of head trauma and ALS was found by several others [20,[23][24][25].”

• cites [20,[23][24][25]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

The multivariate analyses adjusted for sex, age, education, interviewee (patient or surrogate), physical activity, smoking, alcohol, and coffee.

“In each model, data were adjusted for sex, age, education, interviewee (patient/control or surrogate), physical activity (occupational, sport/leisure), smoking, alcohol, and coffee (ever/never).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The possibility that both ALS and trauma could be associated with a common factor cannot be excluded.

“However, as the quality of these studies is suboptimal, the possibility that both ALS and trauma could be associated with a common factor cannot be excluded.”

May combine two claims.

Antecedent trauma, repeated trauma, and severe trauma may be risk factors for ALS.

“Antecedent trauma, repeated trauma, and severe trauma may be risk factors for ALS.”

Classified as probably not a substantial claim.

The association between ALS and physical activity, sport and trauma is still ill-defined.

“However, the association between ALS and physical activity, sport and trauma is still ill-defined [7][8][9][10].”

• cites [7]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [8]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [9]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [10]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Kurland et al. found that retrospective case-control studies gave contradictory results because of selection bias, poor definition of trauma, and non-uniform approach to the period preceding clinical onset.

“Kurland et al. [1] reviewed the early literature and found that retrospective case-control studies gave contradictory results because of selection bias, poor definition of nature and extent of trauma and its chronological relationship to the onset of ALS, and a non-uniform approach to the period preceding the clinical onset of the disease.”

• cites [1]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

For each control, injuries occurring in the same interval as the companion case were excluded.

“For each control, injuries occurring in the same interval as the companion case were also excluded.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The lack of association found by others can be interpreted in light of methodological inadequacies, including referral bias, different methods of enrolment, recall and interview bias.

“The lack of association found by others can be also interpreted in light of methodological inadequacies, including referral bias, different methods of enrolment of cases and controls, recall and interview bias [26][27][28][29].”

• cites [26]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [27]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [28]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [29]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The three groups were similar in mean age (65.2, 65.4, and 65.4 years).

“The mean age (SD) was 65.2 (11.3), 65.4 (11.6), and 65.4 (11.4) years for the three groups.”

Classified as probably not a substantial claim.

Multivariate analysis was used separately for events occurring 5+ years before ALS symptom onset to lower the possibility of including injuries that occurred after biological onset.

“Multivariate analysis was used for all traumatic events and, separately, for events occurred 5+ years before the onset of ALS symptoms (old traumatic events) to lower the possibility to include injuries that might have occurred after the biological onset of the disease.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the European pilot study, the proportion of individuals reporting traumatic events was similar amongst cases and controls, but a higher proportion of ALS patients (34.4 vs. 24.1%) reported repeated traumatic events.

“In that study, the proportion of individuals reporting traumatic events was similar amongst cases and controls.However, a higher proportion of patients with ALS (34.4 vs. 24.1%)reported repeated traumatic events.”

• cites [30]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

The role of trauma in ALS has been repeatedly investigated with conflicting results.

“The role of trauma in amyotrophic lateral sclerosis (ALS) has been repeatedly investigated with conflicting results.”

• cites [1]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

In the only cohort study of ALS after head injury, comprising 821 individuals with traumatic brain injury older than 40 years, there was one patient with ALS (none would have been expected in this small US sample).

“In addition, in the only cohort study of ALS after head injury, comprising 821 individuals who had had a traumatic brain injury and were older than 40 years, there was one patient with ALS (none would have been expected in this small US sample) [25].”

• cites [25]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The study had 80% power to detect an odds ratio of 4 with at least 343 cases and 686 controls, assuming 1% of controls and 3.9% of ALS patients report at least one traumatic event requiring hospitalization.

“The study had to be completed after the enrolment of at least 343 cases and 686 controls under the assumption that 1% of controls and 3.9% of patients with ALS would report at least one traumatic event requiring hospitalization [odds ratio (OR) 4], with a 5% level of significance and 80% power.”

• cites [16]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

An association between injuries to the head, neck, shoulder and/or arm was found by Gallagher and Sanders in 76% of patients with ALS.

“An association between injuries to the head, neck, shoulder and/or arm was also found by Gallagher and Sanders [22] in 76% of patients with ALS”

• cites [22]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Classified as probably not a substantial claim.

Another strength is the characterization of injuries by type, severity, timing, and complications, allowing assessment of time relationships, strength, and biological gradient.

“Another strength of the study is the characterization of injuries, which were defined according to type, severity, timing, and complications, so we could assess the time relationships, strength, and biological gradient of the purported association.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The interviewers were not blinded to the diagnosis and the study hypothesis.

“Last, the interviewers were not blinded to the diagnosis and the study hypothesis.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The major strengths of the study are the representativeness of the ALS population and the large sample size, which may favor generalizability.

“The major strengths are the representativeness of the ALS population and the large sample size, which may favor the generalizability of the study results.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Motor axonal injury has been implicated as a possible mechanism based on cases reported amongst men aged 28 through 43 years at diagnosis.

“motor axonal injury has been implicated as a possible mechanism based on a number of cases reported during a 14-year period amongst men aged 28 through 43 years at the time of diagnosis [31].”

• cites [31]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The definition of trauma used may have excluded mild traumatic injuries.

“Third, our definition of trauma can be questioned, as mild traumatic injuries might have been excluded.”

Probably not a substantial claim: may not pass S2 (checkable).

Given the robustness of the findings, confounding and bias seem unlikely.

“Given the robustness of our findings, confounding and bias seem unlikely.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The possibility that a specific genotype may modify the effects of injuries on motor neurons cannot be excluded.

“In addition, as reported by others [24], the possibility that a specific genotype may modify the effects of injuries on motor neurons cannot be excluded.”

• cites [24]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Patients with newly diagnosed ALS may be less likely to be aware of the purported association between the disease and trauma than patients with more advanced disease.

“On the other hand, patients with newly diagnosed ALS may be less likely to be aware of the purported association between the disease and trauma than patients with more advanced disease.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Pathological evidence has been provided for an association between repetitive head trauma in contact sports and the development of motor neuron disease.

“In addition, pathological evidence has been provided with an association between repetitive head trauma in contact sports and the development of motor neuron disease [36].”

• cites [36]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Hospital controls do not represent the general population.

“First, by definition hospital controls do not represent the general population”

Probably not a substantial claim: may not pass S3 (load-bearing).

Classification of injury severity was based on interviewees' subjective opinions.

“Fourth, classification of the severity of injuries was based on interviewees' subjective opinions.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Data were collected by several investigators and inter-rater reliability is not known.

“Fifth, data were collected by several investigators and inter-rater reliability is not known.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Most cases and their companion controls were interviewed by the same person.

“However, the interviewers had been educated to perform a standardized interrogation of patients or surrogates and most cases, and their companion controls were interviewed by the same person.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The interviewers had been educated to perform a standardized interrogation of patients or surrogates.

“However, the interviewers had been educated to perform a standardized interrogation of patients or surrogates and most cases, and their companion controls were interviewed by the same person.”

Probably not a substantial claim: may not pass S3 (load-bearing).

This perhaps explains why trauma has been reported as a risk factor mostly for limb-onset ALS.

“This perhaps explains why trauma has been reported as a risk factor mostly for limb-onset ALS.”

Classified as probably not a substantial claim.

Adjustment of P-levels for multiple testing was considered unnecessary owing to the exploratory nature of the study.

“Owing to the exploratory nature of this study, adjustment of P-levels for multiple testing was considered unnecessary [17].”

• cites [17]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Men are more likely than women to report traumatic events, repeated injuries, and disabling injuries in their lifetime.

“Men are more likely than women to report traumatic events, repeated injuries, and disabling injuries in their lifetime [38].”

• cites [38]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Repetitive head injury has been associated with chronic traumatic encephalopathy.

“Repetitive head injury has also been associated with chronic traumatic encephalopathy, a progressive tau-opathy causing behavioral and personality changes, parkinsonism and dementia [35].”

• cites [35]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

TDP-43 proteinopathy, thought to mediate the neuronal cytoskeleton's response to axonal injuries, extended from the frontal and temporal cortex to the spinal cord.

“TDP-43 proteinopathy, which is thought to mediate the neuronal cytoskeleton's response to axonal injuries, extended from the frontal and temporal cortex to the spinal cord.”

• cites [36]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

The study used standardized interviews and semi-structured forms to collect information.

“However, we made every effort to collect the required information as accurately as possible using standardized interviews and semi-structured forms.”