Bias due to interval censored outcomes in a study of flare risk after hydroxychloroquine taper/cessation in systemic lupus erythematosus
(2026) In Journal of Clinical Epidemiology 195.- Abstract
Objective This study attempted to quantify the bias expected due to partly interval-censored (IC) outcomes in the estimated association between hydroxychloroquine (HCQ) taper/cessation and time to disease flare among individuals with systemic lupus erythematosus (SLE). Methods Using data-driven simulations, we estimated bias expected due to IC using real-world data from the Systemic Lupus International Collaborating Clinics inception cohort. The time-varying exposure of interest was a binary indicator of HCQ tapering/cessation. The composite outcome was lupus flare, defined as lupus hospitalizations or increases in disease activity or medication dose. The two latter components were IC, as they were recorded only at annual assessment,... (More)
Objective This study attempted to quantify the bias expected due to partly interval-censored (IC) outcomes in the estimated association between hydroxychloroquine (HCQ) taper/cessation and time to disease flare among individuals with systemic lupus erythematosus (SLE). Methods Using data-driven simulations, we estimated bias expected due to IC using real-world data from the Systemic Lupus International Collaborating Clinics inception cohort. The time-varying exposure of interest was a binary indicator of HCQ tapering/cessation. The composite outcome was lupus flare, defined as lupus hospitalizations or increases in disease activity or medication dose. The two latter components were IC, as they were recorded only at annual assessment, without a precise date. For the unknown IC event times, a “true” event time was randomly generated from a uniform distribution of the time between two assessments. Each simulated sample was analyzed separately imputing unknown event times (for IC outcomes) either at the midpoint or endpoint of the interval between the two adjacent yearly assessments. Results of multivariable Cox proportional hazards models, adjusted for demographics, drugs, and clinical variables, using either “true” or imputed IC event times were compared. Results The 1543 SLE patients were followed for a median of 42.2 months. During follow-up, 396 participants tapered/stopped HCQ and 1187 experienced a flare. The adjusted uncorrected hazard ratio was 1.51 (95% confidence interval: 1.30, 1.75) and 1.40 (95% confidence interval: 1.21, 1.62) for midpoint and endpoint imputations, respectively. Data-driven simulations showed that imputation of IC event times resulted in a small but systematic bias toward the null that was consistently larger for endpoint than for midpoint imputation. Conclusions IC events induced bias toward the null in the estimated association between HCQ taper/cessation and lupus flares. Data-driven simulations are useful for quantitative bias analyses in complex situations, as they allow accounting for relevant characteristics of a particular real-world dataset.
(Less)
- author
- organization
- publishing date
- 2026-07
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Data-driven simulations, Hydroxychloroquine, Interval censoring, Pharmacoepidemiologic methods, Quantitative bias analysis, Systemic lupus erythematosus
- in
- Journal of Clinical Epidemiology
- volume
- 195
- article number
- 112261
- publisher
- Elsevier
- external identifiers
-
- pmid:41921830
- scopus:105036681009
- ISSN
- 0895-4356
- DOI
- 10.1016/j.jclinepi.2026.112261
- language
- English
- LU publication?
- yes
- id
- 3bbf89d6-1134-4986-a432-4b5007a7fb34
- date added to LUP
- 2026-06-29 12:14:46
- date last changed
- 2026-06-29 12:15:50
@article{3bbf89d6-1134-4986-a432-4b5007a7fb34,
abstract = {{<p>Objective This study attempted to quantify the bias expected due to partly interval-censored (IC) outcomes in the estimated association between hydroxychloroquine (HCQ) taper/cessation and time to disease flare among individuals with systemic lupus erythematosus (SLE). Methods Using data-driven simulations, we estimated bias expected due to IC using real-world data from the Systemic Lupus International Collaborating Clinics inception cohort. The time-varying exposure of interest was a binary indicator of HCQ tapering/cessation. The composite outcome was lupus flare, defined as lupus hospitalizations or increases in disease activity or medication dose. The two latter components were IC, as they were recorded only at annual assessment, without a precise date. For the unknown IC event times, a “true” event time was randomly generated from a uniform distribution of the time between two assessments. Each simulated sample was analyzed separately imputing unknown event times (for IC outcomes) either at the midpoint or endpoint of the interval between the two adjacent yearly assessments. Results of multivariable Cox proportional hazards models, adjusted for demographics, drugs, and clinical variables, using either “true” or imputed IC event times were compared. Results The 1543 SLE patients were followed for a median of 42.2 months. During follow-up, 396 participants tapered/stopped HCQ and 1187 experienced a flare. The adjusted uncorrected hazard ratio was 1.51 (95% confidence interval: 1.30, 1.75) and 1.40 (95% confidence interval: 1.21, 1.62) for midpoint and endpoint imputations, respectively. Data-driven simulations showed that imputation of IC event times resulted in a small but systematic bias toward the null that was consistently larger for endpoint than for midpoint imputation. Conclusions IC events induced bias toward the null in the estimated association between HCQ taper/cessation and lupus flares. Data-driven simulations are useful for quantitative bias analyses in complex situations, as they allow accounting for relevant characteristics of a particular real-world dataset.</p>}},
author = {{Kaddoura, Rima and Bernatsky, Sasha and Beauchamp, Marie Eve and Guerra, Steve Ferreira and Almeida-Brasil, Celline C. and Hanly, John G. and Urowitz, Murray and Clarke, Ann E. and Ruiz-Irastorza, Guillermo and Gordon, Caroline and Ramsey-Goldman, Rosalind and Petri, Michelle A. and Ginzler, Ellen M. and Wallace, Daniel J. and Bae, Sang Cheol and Romero-Diaz, Juanita and Dooley, Mary Anne and Peschken, Christine and Isenberg, David and Manzi, Susan and Jacobsen, Søren and Lim, S. Sam and Nived, Ola and Jönsen, Andreas and Kamen, Diane L. and Aranow, Cynthia and Sánchez-Guerrero, Jorge and Gladman, Dafna D. and Fortin, Paul R. and Alarcón, Graciela S. and Merrill, Joan T. and Kalunian, Kenneth and Ramos-Casals, Manuel and Zoma, Asad A. and Askanase, Anca D. and Khamashta, Munther and Bruce, Ian N. and Inanc, Murat and Lukusa, Luck and Abrahamowicz, Michal}},
issn = {{0895-4356}},
keywords = {{Data-driven simulations; Hydroxychloroquine; Interval censoring; Pharmacoepidemiologic methods; Quantitative bias analysis; Systemic lupus erythematosus}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Journal of Clinical Epidemiology}},
title = {{Bias due to interval censored outcomes in a study of flare risk after hydroxychloroquine taper/cessation in systemic lupus erythematosus}},
url = {{http://dx.doi.org/10.1016/j.jclinepi.2026.112261}},
doi = {{10.1016/j.jclinepi.2026.112261}},
volume = {{195}},
year = {{2026}},
}