Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose–response meta-analysis

International audienceBackground: A noticeable change of the male-to-female sex ratio (SR) has been observed in Amyotrophic Lateral Sclerosis (ALS) leading to an apparent regression of SR with time (SR close to 1:1). Objective: To provide a global SR estimate and investigate its relation with respect to population age. Methods: A systematic review and meta-analysis was conducted including only population-based studies with a high-quality methodology in European ancestral origin population. Male-to-female SR was estimated by three different measures: SR number, SR crude incidence and SR standardized incidence. Standard and dose-response meta-analyses were performed to assess the pooled SR measures (irrespective of population age) and the evolution of the SR measures with respect to population age, respectively. Potential sources of heterogeneity were investigated via meta-regression. Results: Overall, 3254 articles were retrieved in the literature search. Thirty-nine studies stratified by time periods were included. The overall pooled male-to-female ratio was 1.28 (95% CI 1.23-1.32) for SR number, 1.33 (95% CI 1.29-1.38) for SR crude incidence and 1.35 (95% CI 1.31-1.40) for SR standardized incidence. The SR number with respect to population age reveals a progressive reduction of SR at increasing age, while the SR crude incidence in relation to age displays a U-shaped curve. Conclusions: The number and the incidence of ALS cases were consistently higher in males than females. Dose-response meta-analysis showed that SR measures change with respect to population age. Further original research is needed to clarify if our findings are reproducible in other populations

Age-specific ALS incidence: a dose–response meta-analysis

International audienceTo evaluate the association between worldwide ALS incidence rates and age, using a dose–response meta-analysis. We reviewed Medline and Embase up to July 2016 and included all population-based studies of newly-diagnosed cases, using multiple sources for case ascertainment. A dose–response meta-analysis was performed. A meta-regression investigated potential sources of heterogeneity. Of 3254 articles identified in the literature, we included 41 incidence studies covering 42 geographical areas. Overall, the fit between observed and predicted age-specific rates was very good. The expected variation of ALS incidence with age was characterized, in each study, by a progressive increase in the incidence from the 40s leading to a peak in the 60s or 70s, followed by a sharp decrease. Cochran’s Q test suggested a significant heterogeneity between studies. Overall, estimated patterns of ALS age-specific incidence (at which the peak was reached) were similar among subcontinents of Europe and North America: peak of ALS incidence ranged in these areas between 6.98 and 8.17/100,000 PYFU, which referred to age in the range 71.6–77.4 years. The relationship between age and ALS incidence appeared different for Eastern Asia which was characterized by a peak of ALS incidence at 2.20/100,000 PYFU around 75 years of age. This study confirms the consistency of the age-specific ALS incidence pattern within different subcontinents. Age-specific incidence appears lower in Eastern Asia as compared to Europe and North America

Strong evidence of sexual dimorphic effect of adiposity excess on insulin sensitivity

Aims: Our aims were to investigate in several large samples, with a wide range of adiposity, whether: (1) the effect of BMI on insulin sensitivity is different between sexes; (2) also waist circumference plays a sex-specific role on insulin sensitivity; and (3) serum adiponectin and resistin are mediators of such sex-dimorphic effect. Methods: Samples used were: Gargano study 1 (GS1), GS2 and Catania study (CS) comprising 3274 individuals. Adiponectin and resistin were measured by ELISA. Associations between variables were tested by linear models. Results: In all samples, relationship between BMI and HOMAIR was steeper in males than in females (BMI-by-sex interaction p = 0.04–0.0007). No interaction was observed on serum adiponectin and resistin (p = 0.40–059), which are therefore unlikely to mediate the sex-dimorphic effect of BMI on insulin resistance. Relationship between waist circumference and HOMAIR was similar between sexes in GS1 and GS2 but not in CS (waist-by-sex interaction p = 0.01), comprising much heavier individuals. This suggests that a sex-dimorphic effect of abdominal adiposity on insulin resistance is observable only in the context of high BMI. Conclusions: Our findings represent a proof of concept that BMI and insulin sensitivity are associated in a sex-specific manner. This may explain why females are protected from diabetes and cardiovascular disease, compared to males of similar BMI

Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis.

International audienceTo assess the worldwide variation of amyotrophic lateral sclerosis (ALS) incidence, we performed a systematic review and meta-analysis of population-based data published to date. We reviewed Medline and Embase up to June 2015 and included all population-based studies of newly diagnosed ALS cases, using multiple sources for case ascertainment. ALS crude and standardized incidence (on age and sex using the US 2010 population) were calculated. Random effect meta-analysis and meta-regression were performed using the subcontinent as the main study level covariate. Sources of heterogeneity related to the characteristics of the study population and the study methodology were investigated. Among 3216 records, 44 studies were selected, covering 45 geographical areas in 11 sub-continents. A total of 13 146 ALS cases and 825 million person-years of follow-up (PYFU) were considered. The overall pooled worldwide crude ALS incidence was at 1.75 (1.55-1.96)/100 000 PYFU; 1.68 (1.50-1.85)/100 000 PYFU after standardization. Heterogeneity was identified in ALS standardized incidence between North Europe [1.89 (1.46-2.32)/100 000 PYFU] and East Asia [0.83 (0.42-1.24)/100 000 PYFU, China and Japan P = 0.001] or South Asia [0.73 (0.58-0.89)/100 000/PYFU Iran, P = 0.02]. Conversely, homogeneous rates have been reported in populations from Europe, North America and New Zealand [pooled ALS standardized incidence of 1.81 (1.66-1.97)/100 000 PYFU for those areas]. This review confirms a heterogeneous distribution worldwide of ALS, and sets the scene to sustain a collaborative study involving a wide international consortium to investigate the link between ancestry, environment and ALS incidence

Comparison of the ability of the King’s and MiToS staging systems to predict disease progression and survival in amyotrophic lateral sclerosis

International audienceBackground: Assessing clinical progression in amyotrophic lateral sclerosis (ALS) remains a challenge. We evaluated the validity and predictive capabilities of the King’s and Milano-Torino Staging (MiToS) systems in a cohort of patients with ALS to demonstrate their benefit in clinical practice.Methodology: A cohort study was performed by including ALS incident cases in a referral center from 2007 to 2016. The staging systems were determined at time of diagnosis and follow-up. The standardized median times to reach each stage were computed. A multi-state model in the framework of the Cox model evaluated the predictive value of measurements. The survival C-statistic was reported as a measure of prediction ability.Results: Overall, 298 incident cases were included. The King’s and MiToS systems described a progressive increase in the risk of dying with each elapsed stage. However, a lower resolution for late disease description for the King’s system was observed, and late stages overlapped for the MiToS system. Slight variations in the staging systems appeared to improve performance based on validity and prediction abilities: (i) in the King’s (C-statistic ¼ 0.783), by adding a new stage involving the need for both gastrostomy and NIV: (ii) in the MiToS (C-statistic ¼ 0.792), by merging stage 3 and stage 4 into a single stage 3.Conclusion: Both King’s and MiToS are valid systems but have certain limitations. Variations in the staging systems may provide a more suitable framework for describing progression and survival. Further research is needed to evaluate the variations in the staging systems