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Updated: Sep 30, 2025

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Selecting External Controls for Internal Cases Using Stratification Score Matching Methods.

Stefanie A Busgang1, Lance A Waller2, Elena Colicino1

  • 1Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

International Journal of Environmental Research and Public Health
|March 10, 2022
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External controls matched using stratification score (SS) matching can effectively substitute for internal controls in rare disease research. This method offers comparable bias reduction, proving valuable when internal controls are unavailable for environmental exposure studies.

Keywords:
external controlsregistry-basedstratification score matching

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Area of Science:

  • Environmental Epidemiology
  • Biostatistics
  • Rare Disease Research

Background:

  • Rare disease registries are crucial for studying environmental exposures but often lack adequate healthy control groups.
  • Defining surrogate control groups matched on confounding variables is essential for valid exposure-disease association studies.
  • Stratification score (SS) matching is a statistical technique used to balance covariates between case and control groups.

Purpose of the Study:

  • To evaluate the efficacy of externally selected controls, matched via SS matching, as proxies for internal controls.
  • To compare the association between methyl paraben (MEPB) exposure and autism spectrum disorder (ASD) using both externally and internally matched controls.
  • To determine if SS matching with external controls can achieve similar bias reduction as internal controls.

Main Methods:

  • Utilized 225 autism spectrum disorder (ASD) cases and 241 internal controls from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study.
  • Selected 265 external controls from the National Health and Nutrition Examination Survey (NHANES) (2005-2016).
  • Calculated SSs using demographic covariates and performed 1:1 matching without replacement; compared MEPB-ASD associations between externally matched and internally matched cohorts.

Main Results:

  • The distribution of covariates and mean squared error of paired differences (MSEpaired) in SSs were similar between internal (0.007) and external (0.011) control groups.
  • The association between methyl paraben (MEPB) and autism spectrum disorder (ASD) was comparable when using externally matched controls versus internally matched controls.
  • External controls selected via SS matching demonstrated similar bias reduction capabilities compared to internal controls.

Conclusions:

  • Externally selected controls, when matched using stratification score (SS) matching, can serve as effective proxies for internal controls in rare disease studies.
  • SS matching with external controls provides a viable and comparable bias reduction strategy, particularly when internal controls are scarce or unavailable.
  • This approach enhances the utility of rare disease registries for environmental exposure research by enabling robust case-control comparisons.