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Multiple Imputation in Genetic Studies: Assessing Response to MTX Treatment

This study explores the application of multiple imputation techniques for addressing missing data in the context of assessing the effectiveness of methotrexate (MTX) treatment. Utilizing DNA and various clinical covariates (e.g., active joints, general well-being), the research aims to identify SNPs linked to the patient response to MTX over six months. Key outcomes include defining improvement and response rates based on different thresholds. The implications for clinical improvement assessment and potential methodologies for analyzing missing data are also discussed.

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Multiple Imputation in Genetic Studies: Assessing Response to MTX Treatment

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  1. Missing Data ll

  2. Multiple Imputation • Essentially, the replacement of one individual with another randomly selected individual from a defined population • Works under MAR and MCAR assumptions • Eg. Identifying predictive value of a diagnostic test

  3. Response to MTX • Aim: • Identify SNPs associated with MTX response

  4. Response to MTX • Data collected at baseline and at six months • Includes: • DNA • Clinical covariates: Active Joints, Limited Joints, General Well Being (GW), Physician’s Global assessment (Glob), CHAQ, ESR

  5. Response to MTX • Defining improvement: • Percentage change over 6 months (Negative Δ% indicates improvement) • ACR criteria: “At least 30% improvement from baseline in 3 of any 6 variables, with no more than 1 of the remaining variables worsening by 30%” • Extends to 50% and 70% • Four main outcomes • Improvement (30%, 50%, 70%) • Remain the same • No Response (30%) • Missing • Problems?

  6. Response to MTX Examples T1 – T0 T0

  7. Response to MTX Example: 6 COV’s + Missing data

  8. Response to MTX • Problems: • Division by 0 at baseline • Missing data at different t • Solutions?

  9. Analysis • Genes, COV • Multiple Imputation • Logistic regression

  10. Analysis • Genes • AMPD1 • ATIC • DHFR • ITPA • SLC19A1 • SLC16A7 • 50 SNPs • Carriage of the minor allele

  11. Multiple Imputation

  12. Results

  13. Conclusions • Limitation in response definition • Do not reflect clinical/overall improvement • Solutions: • New definition calculated using PCA or Factor analysis?

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