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Latent Class Analysis Identifies Distinctive Behavioral Subtypes in Children with Fragile X Syndrome

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Abstract

Fragile X syndrome (FXS) is characterized by variable neurobehavioral abnormalities, which leads to difficulties in developing and evaluating treatments and in determining accurate prognosis. We employed a pediatric cross-sectional sample (1,072 males, 338 females) from FORWARD, a clinic-based natural history study, to identify behavioral subtypes by latent class analysis. Input included co-occurring behavioral conditions, sleep and sensory problems, autistic behavior scales (SCQ, SRS-2), and the Aberrant Behavior Checklist revised for FXS (ABCFX). A 5-class solution yielded the most clinically meaningful, pharmacotherapy independent behavioral groups with distinctive SCQ, SRS-2, and ABCFX profiles, and adequate non-overlap (≥ 71%): “Mild” (31%), “Moderate without Social Impairment” (32%), “Moderate with Social Impairment” (7%), “Moderate with Disruptive Behavior” (20%), and “Severe” (9%). Our findings support FXS subtyping, for improving clinical management and therapeutic development.

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Acknowledgments

We would like to thank everyone involved in the FORWARD project, in particular the participating patients and their families. FORWARD Consortium Elizabeth Berry-Kravis (Rush University Medical Center), Milen Velinov (Rutgers Robert Wood Johnson Medical School), Amy L. Talboy (Emory University School of Medicine), Stephanie L. Sherman (Emory University School of Medicine), Walter E. Kaufmann (Emory University School of Medicine), Marcy Schuster (Elwyn Inc.), Nicole Tartaglia (Children’s Hospital Colorado), Robyn A. Filipink (University of Pittsburgh School of Medicine), Dejan B. Budimirovic (Kennedy Krieger Institute, Johns Hopkins Medical Institutions), Deborah Barbouth (University of Miami, Miller School of Medicine), Amy Lightbody (Stanford University School of Medicine), Allan Reiss (Stanford University School of Medicine), Carol M. Delahunty (The Metrohealth System, Cleveland), Randi J. Hagerman (MIND Institute, University of California Davis Medical Center), David Hessl (MIND Institute, University of California Davis Medical Center), Craig A. Erickson (Cincinnati Children’s Hospital Medical Center), Gary Feldman (Miller Children’s & Woman’s Hospital), Jonathan D. Picker (Boston Children’s Hospital), Ave M. Lachiewicz (Duke Health Center, Lenox Baker Children’s Hospital), Holly K. Harris (Baylor College of Medicine & Meyer Center for Developmental Pediatrics), Amy Esler (University of Minnesota), Richard E. Frye (Barrow Neurological Institute at Phoenix Children’s Hospital), Patricia A. Evans (University of Texas Southwestern Medical Center), Mary Ann Morris (University of Texas Southwestern Medical Center), Barbara A. Haas-Givler (Geisinger’s Autism & Developmental Medicine Institute), Andrea L. Gropman (Children’s National Medical Center), Ryan S. Uy (Children’s National Medical Center), Reymundo Lozano (Icahn School of Medicine at Mount Sinai), Carrie Buchanan (Greenwood Genetic Center), Jean A. Frazier (Eunice Kennedy Shriver Center, University of Massachusetts Medical School), Stephanie M. Morris (Washington University in St. Louis).

Funding

The present study was supported by cooperative agreements #U01DD000231, #U19DD000753, and # U01DD001189, and contract 75D30120F09737, funded by the Centers for Disease Control and Prevention (CDC). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Department of Health and Human Services.

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Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

    Walter E. Kaufmann

  2. RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709, USA

    Melissa Raspa, Carla M. Bann & Julia M. Gable

  3. Texas Children’s Hospital, 8080 North Stadium Drive, Houston, TX, 77054, USA

    Holly K. Harris

  4. Kennedy Krieger Institute, 1741 Ashland Avenue, Baltimore, MD, 21205, USA

    Dejan B. Budimirovic

  5. Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA

    Reymundo Lozano

Authors
  1. Walter E. Kaufmann
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  2. Melissa Raspa
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  3. Carla M. Bann
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  4. Julia M. Gable
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  5. Holly K. Harris
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  6. Dejan B. Budimirovic
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  7. Reymundo Lozano
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Consortia

FORWARD Consortium

  • Elizabeth Berry-Kravis
  • , Milen Velinov
  • , Amy L Talboy
  • , Stephanie L Sherman
  • , Walter E Kaufmann
  • , Marcy Schuster
  • , Nicole Tartaglia
  • , Robyn A Filipink
  • , Dejan B Budimirovic
  • , Deborah Barbouth
  • , Amy Lightbody
  • , Allan Reiss
  • , Carol M Delahunty
  • , Randi J Hagerman
  • , David Hessl
  • , Craig A Erickson
  • , Gary Feldman
  • , Jonathan D Picker
  • , Ave M Lachiewicz
  • , Holly K Harris
  • , Amy Esler
  • , Richard E Frye
  • , Patricia A Evans
  • , Mary Ann Morris
  • , Barbara A Haas-Givler
  • , Andrea L Gropman
  • , Ryan S Uy
  • , Reymundo Lozano
  • , Carrie Buchanan
  • , Jean A Frazier
  •  & Stephanie M Morris

Contributions

WEK and MR conceived the project and supervised all study efforts. WEK led data analysis and interpretation, and manuscript drafting. CMB had a primary role in data analysis and assisted with data interpretation and drafting the manuscript. JMG helped with data analysis. HKH, DBB, and RL helped with data interpretation and drafting the manuscript. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Walter E. Kaufmann.

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Competing interest

WEK is Chief Scientific Officer of Anavex Life Sciences Corp. HKH is a co-investigator on clinical trials funded by Ionis Pharmaceuticals, Neuren Pharmaceuticals and Clinical Research Associates, LLC. DBB has been principal investigator on clinical trials funded by Ovid Therapeutics and Zynerba Pharmaceuticals; he has also consulted for Ovid Therapeutics. The other co-authors declare that they have no competing interests.

Ethical approval

The Institutional Review Board at every participating site provided approval and oversight to ensure ethical conduct of human subjects research throughout the study. Informed consent was provided by all parents/guardians who participated. Consent or assent was provided by participants with fragile X syndrome, depending on age and consenting capacity as determined by the Institutional Review Boards.

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The members of the FORWARD consortium are listed in acknowledgments.

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Kaufmann, W.E., Raspa, M., Bann, C.M. et al. Latent Class Analysis Identifies Distinctive Behavioral Subtypes in Children with Fragile X Syndrome. J Autism Dev Disord 54, 725–737 (2024). https://doi.org/10.1007/s10803-022-05821-7

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