I have personally seen more than 2,000 patients with ALS in the past 16 years. I believe the variability in the disease holds important clues to figuring out how to slow, stop, or reverse it. This interesting paper suggests that variations in two genes, IDE and CAMTA1, are associated with slightly longer survival. If this finding is real, then understanding what these genes do may help us develop drugs that slow the progression of ALS.
The major strength of this paper is its large sample size. This multinational group of authors should be commended for their collaboration.
There are, however, some weaknesses. The biggest one is that the model used did not account for between-patient variability in the use of treatments known to affect survival such as riluzole, multidisciplinary care, and most importantly non-invasive ventilation (which has the largest effect on survival). The authors argue that stratification by country reduced the risk of bias from riluzole and multidisciplinary clinic use. It is not clear to me that stratification by country can correct this issue. In my opinion, this study will need to be repeated using a model that accounts for these three treatments. As with all ALS studies, there is likely to be a referral bias here since only a small percentage of patients enroll, and these patients may be different from those who do not enroll. This will create problems with generalizability. It is likely that ALS patients with the most extreme (and interesting) phenotype—those who stop progressing or even reverse with recovery of lost motor function—were not included in this study since many of them no longer attend ALS clinics. Finally, it is disappointing that the effect size for each of these genes was so small (hazard ratios less than 2) and that this study could not replicate the findings of previous work that suggested variations in Kifap3, EphA1, and/or DAO genes might influence survival.
I look forward to seeing this study replicated using a model that accounts for treatments that can effect survival. Even more, I look forward to a study that focuses on extreme ALS phenotypes including patients whose disease seems to stop progressing or reverses with recovery of lost motor functions.
Comments
Duke University
I have personally seen more than 2,000 patients with ALS in the past 16 years. I believe the variability in the disease holds important clues to figuring out how to slow, stop, or reverse it. This interesting paper suggests that variations in two genes, IDE and CAMTA1, are associated with slightly longer survival. If this finding is real, then understanding what these genes do may help us develop drugs that slow the progression of ALS.
The major strength of this paper is its large sample size. This multinational group of authors should be commended for their collaboration.
There are, however, some weaknesses. The biggest one is that the model used did not account for between-patient variability in the use of treatments known to affect survival such as riluzole, multidisciplinary care, and most importantly non-invasive ventilation (which has the largest effect on survival). The authors argue that stratification by country reduced the risk of bias from riluzole and multidisciplinary clinic use. It is not clear to me that stratification by country can correct this issue. In my opinion, this study will need to be repeated using a model that accounts for these three treatments. As with all ALS studies, there is likely to be a referral bias here since only a small percentage of patients enroll, and these patients may be different from those who do not enroll. This will create problems with generalizability. It is likely that ALS patients with the most extreme (and interesting) phenotype—those who stop progressing or even reverse with recovery of lost motor function—were not included in this study since many of them no longer attend ALS clinics. Finally, it is disappointing that the effect size for each of these genes was so small (hazard ratios less than 2) and that this study could not replicate the findings of previous work that suggested variations in Kifap3, EphA1, and/or DAO genes might influence survival.
I look forward to seeing this study replicated using a model that accounts for treatments that can effect survival. Even more, I look forward to a study that focuses on extreme ALS phenotypes including patients whose disease seems to stop progressing or reverses with recovery of lost motor functions.
View all comments by Richard BedlackMake a Comment
To make a comment you must login or register.