Predictors of survival in patients with amyotrophic lateral sclerosis: A large meta-analysis

Su, Wei‐Ming; Cheng, Yiming; Jiang, Zheng; Duan, Qing-Qing; Yang, Tianmi; Shang, Huifang; Chen, Yongping

doi:10.1016/j.ebiom.2021.103732

Cited by 44 publications

(34 citation statements)

References 67 publications

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“…Here, after synthesizing a total of 40 comparisons, we found C9orf72 expansion was also associated with shorter survival (HR:1.6, 95%CI [1.4, 1.9]). In addition, cases with C9orf72 expansion may have a more rapid rate of cognitive decline and a higher risk of developing FTD [ 114 ], which were predictors for poor prognosis for ALS as well [ 5 ]. So far, gene therapy targeting C9orf72 has been carried out in preclinical studies [ 115 , 116 ], and these methods are promising approaches for future in vivo studies.…”

Section: Discussionmentioning

confidence: 99%

“…Besides, some studies did not report the HR directly, when we get HR from the survival curve, there may be some slight gap with the accurate results. Some differences in follow-up time, the included population, and the definition of outcomes may lead to publication bias and the non-genetic factors related to ALS survival may also play a role [ 5 ]. Moreover, the lack of commonality of prognostic factors investigated in different cox PH models is also a limitation, and some studies are single-factor analyses and did not adjust for confounding factors.…”

Section: Discussionmentioning

confidence: 99%

“…According to previous survival research in ALS, survival was defined as the time between the onset of symptoms and noninvasive ventilation (NIV) for more than 23 hours per day, or tracheostomy or death [ 5 , 17 , 18 ]. The inclusion criteria are as follows: (1) assessed the association between present or absence with different genetic loci and survival time from the onset in patients with ALS; (2) had reported a hazard ratio (HR) and 95% confidential intervals (CI) for patients with genetic mutations or Kaplan-Meier plots from which we can estimate the HR and 95%CI; (3) abstract, reviews, letters without original study, secondary studies and studies that HR or 95%CI was unavailable in papers, excluded from the analysis; and (4) full papers published in English.…”

Section: Methodsmentioning

confidence: 99%

“…Hence, more attention has been paid to the associated factors that affect the survival time. In our recent study, twenty-five non-genetic factors associated with ALS survival were identified, such as age at onset, onset site, the time between onset and diagnosis, et al [ 5 ]. However, these non-genetic factors associated with ALS survival could be affected by confounding factors.…”

Section: Introductionmentioning

confidence: 99%

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Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis

Duan

et al. 2022

BMC Med

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Background The time of survival in patients with amyotrophic lateral sclerosis (ALS) varies greatly, and the genetic factors that contribute to the survival of ALS are not well studied. There is a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS. Methods The published studies were systematically searched and obtained from PubMed, EMBASE, and the Cochrane Library without any language restrictions from inception to Oct 27, 2021. A network meta-analysis for ALS causative/risk genes and a systematic review and pairwise meta-analysis for other genetic modifiers were conducted. The PROSPERO registration number: CRD42022311646. Results A total of 29,764 potentially relevant references were identified, and 71 papers were eligible for analysis based on pre-decided criteria, including 35 articles in network meta-analysis for 9 ALS causative/risk genes, 17 articles in pairwise meta-analysis for four genetic modifiers, and 19 articles described in the systematic review. Variants in three genes, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR:1.8), were associated with short survival of ALS, but such association was not identified in SOD1, TARDBP, TBK1, NEK1, UBQLN2, and CCNF. In addition, UNC13A rs12608932 CC genotype and ZNF521B rs2275294 C allele also caused a shorter survival of ALS; however, APOE ε4 allele and KIFAP3 rs1541160 did not be found to have any effect on the survival of ALS. Conclusions Our study summarized and contrasted evidence for prognostic genetic factors in ALS and would help to understand ALS pathogenesis and guide clinical trials and drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis

Duan

et al. 2022

BMC Med

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“…These complications result in a late diagnosis, after the underlying pathology is already well underway. The universal prognosis of about two to 5 years left to live post-diagnosis is evidence of this fact ( Knibb et al, 2016 ; Su et al, 2021 ). There is a dire need to establish an earlier diagnosis of ALS so that those with the disease can have a fighting chance at earlier therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

Novel Genetic Signatures Associated With Sporadic Amyotrophic Lateral Sclerosis

Logan

Dubel-Haag²,

Schcolnicov³

et al. 2022

Front. Genet.

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Amyotrophic Lateral Sclerosis (ALS) is a complex polygenetic neurodegenerative disorder. Establishing a diagnosis for ALS is a challenging and lengthy process. By the time a diagnosis is made, the lifespan prognosis is only about two to 5 years. Genetic testing can be critical in assessing a patient’s risk for ALS, provided they have one of the known familial genes. However, the vast majority of ALS cases are sporadic and have no known associated genetic signatures. Our analysis of the whole genome sequencing data from ALS patients and healthy controls from the Answer ALS Consortium has uncovered twenty-three novel mutations in twenty-two protein-coding genes associated with sporadic ALS cases. The results show the majority of patients with the sporadic form of ALS have at least one or more mutation(s) in the 22 genes we have identified with probabilities of developing ALS ranging from 25–99%, depending on the number of mutations a patient has among the identified genes. Moreover, we have identified a subset of the ALS cohort that has >17 mutations in the 22 identified. In this case, a patient with this mutation profile has a 99% chance of developing ALS and could be classified as being at high risk for the disease. These genetic biomarkers can be used as an early ALS disease diagnostic tool with a rapid and non-invasive technique.

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Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers

et al. 2022

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ImportanceClinical trial activity in amyotrophic lateral sclerosis (ALS) is dramatically increasing; as a result, trial modifications have been introduced to improve efficiency, outcome measures have been reassessed, and considerable discussion about the level of data necessary to advance a drug to approval has occurred. This review discusses what recent pivotal studies can teach the community about these topics.ObservationsBy restricting inclusion and exclusion criteria, recent trials have enrolled populations distinct from previous studies. This has led to efficacy signals being observed in studies that are smaller and shorter than was thought feasible previously. However, such trials raise questions about generalizability of results. Small trials with equivocal clinical results also raise questions about the data necessary to lead to regulatory approval. The ALS Functional Rating Scale–Revised remains the most commonly used primary outcome measure; this review discusses innovations in its use. Blood neurofilament levels can predict prognosis in ALS and may be a sensitive indicator of biologic effect; current knowledge does not yet support its use as a primary outcome.Conclusions and RelevanceIt is now possible to use specific inclusion criteria to recruit a homogeneous patient population progressing at a specific rate; this will likely impact trials in the future. Generalizability of results on limited populations remains a concern. Although clinical outcomes remain the most appropriate primary outcome measures, fluid markers reflecting biologically important processes will assume more importance as more is learned about the association between such markers and clinical end points. The benefit of use of analytic strategies, such as responder analyses, is still uncertain.

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Predictors of survival in patients with amyotrophic lateral sclerosis: A large meta-analysis

Cited by 44 publications

References 67 publications

Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis

Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis

Novel Genetic Signatures Associated With Sporadic Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers

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