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Proteinuria testing among patients with diabetes mellitus is associated with bladder cancer diagnosis: potential for unmeasured confounding in studies of pioglitazone and bladder cancer

Authors

  • James D. Lewis,

    Corresponding author
    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
    3. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    • Correspondence to: J. D. Lewis, MD, MSCE, 720 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104. Email: lewisjd@mail.med.upenn.edu

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  • Laurel Habel,

    1. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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  • Charles Quesenberry,

    1. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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  • Ronac Mamtani,

    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Tiffany Peng,

    1. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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  • Warren B. Bilker,

    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
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  • Monique Hedderson,

    1. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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  • Lisa Nessel,

    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
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  • David J. Vaughn,

    1. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Brian L. Strom,

    1. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA
    2. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
    3. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    4. Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA
    Current affiliation:
    1. Rutgers Biomedical and Health Sciences, Rutgers University, New Brunswick, NJ, USA
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  • Assiamira Ferrara

    1. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
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ABSTRACT

Background

The observed association between pioglitazone and bladder cancer could be causal or because of bias in the design of prior studies. We hypothesize that proteinuria testing may lead to detection bias if routine test results for proteinuria lead to a full urinalysis.

Methods

We reanalyzed patients with diabetes mellitus within Kaiser Permanente Northern California. Logistic and Cox regression adjusted for age, sex, race, and smoking were used to assess the association of proteinuria testing with pioglitazone use, subsequent full urinalysis, and diagnosis with bladder cancer.

Results

Patients treated with pioglitazone were more likely than others with diabetes to undergo testing for proteinuria (p < 0.001). The odds of positive tests for proteinuria were higher among pioglitazone-treated patients (OR = 1.41, 95%CI 1.36–1.46). A positive proteinuria test was associated with increased odds of completing a urinalysis in the following 6 months (OR = 1.78, 95%CI 1.73–1.85). Negative and positive proteinuria test results were inversely (hazard ratio (HR) 0.63, 95%CI 0.52–0.75) and positively associated (HR 2.45, 95%CI 2.12–2.82) with bladder cancer risk, respectively. Adjustment for negative and positive proteinuria testing reduced the magnitude of association between pioglitazone and bladder cancer by only 5 to 10% (ever-exposed HR: from 1.06 to 1.01 and >4 years exposure HR: from 1.38 to 1.28).

Conclusions

Proteinuria testing may be a confounder in studies of pioglitazone and bladder cancer but does not fully explain the association between pioglitazone and bladder cancer in this cohort. Optimal adjustment for proteinuria testing likely requires knowledge of the test result. Copyright © 2014 John Wiley & Sons, Ltd.

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