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

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Abstract

Background

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.

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Data availability

The data for the analyses described in this paper are available by request from the authors.

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Acknowledgements

We thank the following main authors or co-authors of population-based articles who answered our solicitation and for the useful material that they were able to provide: Kari Murros, Poul Joensen, Raeburn Forbes, Robert Swingler (the Scottish MND Register is funded by MND Scotland and supported by the Anne Rowling Regenerative Neurology Clinic), Ibrahim Imam, James Rooney, Albert Ludolph, Gabriele Nagel, Marwa Elamin, Ammar Al-Chalabi, Orla Hardiman, Mark Heverin, Mark Huisman, Joachim Wolf, Adriano Chio, Federica Pisa, Jessica Mandrioli, Monica Bandettini, Stefano Zocollela, Maura Pugliatti, Leslie Parish, Paolo Ragonese, Valerie Mc Guire, Will Longstreth, Eric J. Sorenson, Farrah Mateen, James D. Bonaparte, Cristina Vazquez, Carlos Ketzoian, Kurupath Radhakrishnan, Chien-Hsu Lai, Chung Yan G Fong, Hitoshi Okumura, Tameko Kihira, Bruce Taylor and A Lannuzel. We thank Paul Mehta, Heather Jordan and Jhaqueline Valle for providing data to calculate US incidence. The data came from surveillance projects funded by the Agency for Toxic Substances and Disease Registry’s (ATSDR) National ALS Registry [www.cdc.gov/als] (Contract #200-2009- 32577 and Contract #200-2010-F-36614). We also thank Walter Rocca and Brandon R. Grossardt for the detailed data on Olmsted county population with which they provided us, and Hidenao Sasaki, Robert Miller and Eric Denys as contact persons. We thank Vanna Pistotti for her advice during the literature search, as well as Mineko Terao, Lorenzo Moja and Claudio Pelucchi. We thank Limoges teaching hospital for its grant initiative for mobility.

Funding

This research received no specific Grant from any funding agency in the public, commercial or not-for-profit sectors.

Author information

Author notes

  1. Andrea Fontana and Benoit Marin contributed equally to this work.

Authors and Affiliations

  1. Unit of Biostatistics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy

    Andrea Fontana & Massimilano Copetti

  2. Ministère de la Sante et des Solidarités, Cellule Interministérielle Recherche MSS/MESRI, Paris, France

    Benoit Marin

  3. INSERM, Univ. Limoges, CHU Limoges, IRD, U1094 Tropical Neuroepidemiology, Institute of Epidemiology and Tropical Neurology, GEIST, Limoges, France

    Jaime Luna, Farid Boumédiene, Pierre-Marie Preux & Philippe Couratier

  4. CHU Limoges, Department of Neurology, ALS Expert Center, Limoges, France

    Jaime Luna & Philippe Couratier

  5. Laboratorio di Malattie Neurologiche, Istituto di Ricerche Farmacologiche Mario Negri, Milano IRCCS, Milan, Italy

    Ettore Beghi

  6. Unit of Neurodegenerative Diseases, Department of Clinical Research in Neurology, University of Bari “Aldo Moro”, at “Pia Fondazione Cardinale G. Panico”, 73039, Tricase, Lecce, Italy

    Giancarlo Logroscino

  7. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari, Italy

    Giancarlo Logroscino

  8. CHU Limoges, Centre d’Epidémiologie, de Biostatistique et de Méthodologie de la Recherche, Limoges, France

    Pierre-Marie Preux

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  1. Andrea Fontana
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Contributions

All authors contributed significantly to this paper. Conceptualization: AF, BM, MC; data curation: AF, BM; statistical analysis: AF, BM; interpretation; AF, BM, JL; writing-original draft: AF, BM, JL; all authors reviewed the first draft. All authors contributed to the final manuscript in terms of intellectual content.

Corresponding author

Correspondence to Benoit Marin.

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Conflicts of interest

Andrea Fontana, Benoit Marin, Jaime Luna, Giancarlo Logroscino, Farid Boumédiene, Pierre-Marie Preux, Philippe Couratier and Massimilano Copetti declare no disclosures relevant to the manuscript. Ettore Beghi declares to collaborate with the Italian Ministry of Health, SOBI, Arvelle Therapeutics and the American ALS Association.

Ethical approval

As this review of the literature/meta-analysis does not involve ALS patients but makes use of publications concerning ALS, informed consent of patients is not applicable. Not even approval of an ethics committee is applicable.

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Fontana, A., Marin, B., Luna, J. et al. Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose–response meta-analysis. J Neurol 268, 2973–2984 (2021). https://doi.org/10.1007/s00415-021-10464-2

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  • DOI: https://doi.org/10.1007/s00415-021-10464-2

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