Toward improved statistical methods for analyzing Cotinine-Biomarker health association data
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Department of Epidemiology and Public Health at Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA
Sylvester Comprehensive Cancer Center at Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA
Department of Internal Medicine, Kaiser Permanente, Los Angeles, California, USA
European Centre of Environment and Human Health (ECEHH), Peninsula College of Medicine and Dentistry, Truro, Cornwall, UK
Submission date: 2011-03-18
Acceptance date: 2011-10-03
Publication date: 2011-10-03
Corresponding author
Tulay Koru-Sengul   

Department of Epidemiology and Public Health at Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA
Tobacco Induced Diseases 2011;9(October):11
Serum cotinine, a metabolite of nicotine, is frequently used in research as a biomarker of recent tobacco smoke exposure. Historically, secondhand smoke (SHS) research uses suboptimal statistical methods due to censored serum cotinine values, meaning a measurement below the limit of detection (LOD).

We compared commonly used methods for analyzing censored serum cotinine data using parametric and non-parametric techniques employing data from the 1999-2004 National Health and Nutrition Examination Surveys (NHANES). To illustrate the differences in associations obtained by various analytic methods, we compared parameter estimates for the association between cotinine and the inflammatory marker homocysteine using complete case analysis, single and multiple imputation, “reverse” Kaplan-Meier, and logistic regression models.

Parameter estimates and statistical significance varied according to the statistical method used with censored serum cotinine values. Single imputation of censored values with either 0, LOD or LOD/√2 yielded similar estimates and significance; multiple imputation method yielded smaller estimates than the other methods and without statistical significance. Multiple regression modelling using the “reverse” Kaplan-Meier method yielded statistically significant estimates that were larger than those from parametric methods.

Analyses of serum cotinine data with values below the LOD require special attention. “Reverse” Kaplan-Meier was the only method inherently able to deal with censored data with multiple LODs, and may be the most accurate since it avoids data manipulation needed for use with other commonly used statistical methods. Additional research is needed into the identification of optimal statistical methods for analysis of SHS biomarkers subject to a LOD.

Schisterman EF, Little RJ: Opening the black box of biomarker measurement error. Epidemiology. 2010, 21 (Suppl 4): S1-S3.
Helsel D: Nondetects and Data Analysis: Statistics for Censored Environmental Data. 2005, John Wiley & Sons.
Helsel DR: Fabricating data: How substituting values for nondetects can ruin results, and what can be done about it. Chemosphere. 2006, 65: 2434-2439.
Krishnamoorthy K, Mallick A, Mathew T: Model based imputation approach for data analysis in the presence of nondetectable values: Normal and Related Distributions. Annals of Occupational Hygiene. 2009, 59: 249-261.
Armstrong BG: Effect of measurement error on epidemiological studies of environmental and occupational exposures. Occupational and Environmental Medicine. 1998, 55: 651-656.
Rothman KJ: Methodologic frontiers in environmental epidemiology. Environmental Health Perspectives. 1993, 101 (Suppl 4): 19-21. 10.1289/ehp.93101s419.
Clark JD, Wilkinson JD, LeBlanc WG, Dietz NA, Arheart KL, Fleming LE, Lee DJ: Inflammatory markers and secondhand tobacco smoke exposure among U.S. workers. American Journal of Industrial Medicine. 2008, 51: 626-632.
Benowitz NL, Bernert JT, Caraballo RS, Holiday DB, Wang J: Optimal serum cotinine levels for distinguishing cigarette smokers and nonsmokers within different racial/ethnic groups in the United States between 1999 and 2004. American Journal of Epidemiology. 2009, 169: 236-248.
NHANES, Laboratory Procedures Manual. 2001, [].
Little RJ, Rubin DB: Statistical Analysis with Missing Data. Wiley Series in Probability and Statistics. 2002, Second.
Donders AR, van der Heijden GJ, Stijnen T, Moons KG: Review: a gentle introduction to imputation of missing values. Journal of Clinical Epidemiology. 2006, 59: 1087-1091.
Barnard J, Meng XL: Applications of multiple imputation in medical studies: from AIDS to NHANES. Statistical Methods in Medical Research. 1999, 8: 17-36.
Harel O, Zhou XH: Multiple imputation: review of theory, implementation and software. Statistics in Medicine. 2007, 26: 3057-3077.
Rubin D: Multiple Imputation For Nonresponse In Surveys. 1987, John Wiley & Sons Inc.
Schafer JL: Analysis of Incomplete Multivariate Data. CRC Monographs on Statistics & Applied Probability. 1997.
Schafer J: Analyzing the NHANES III Multiply Imputed Data Set: Methods and examples. 2001, [].
Gillespie BW, Chen Q, Reichert H, Franzblau A, Hedgeman E, Lepkowski J, Adriaens P, Demond A, Luksemburg W, Garabrant DH: Estimating Population Distributions When Some Data Are Below a Limit of Detection by Using a Reverse Kaplan-Meier Estimator. Epidemiology. 2010, 21: S64-S70.
Albert PS, Harel O, Perkins N, Browne R: Use of Multiple Assays Subject to Detection Limits With Regression Modeling in Assessing the Relationship Between Exposure and Outcome. Epidemiology. 2010, 21: S35-S43.
The Third National Health and Nutrition Examination Survey, (NHANES III, 1988-1994). Multiply Imputed Data Set (Series 11, No. 7A). Accessed 7/7/11, [].
Phthalate and bisphenol A exposure among pregnant women in Canada — Results from the MIREC study
Tye E. Arbuckle, Karelyn Davis, Leonora Marro, Mandy Fisher, Melissa Legrand, Alain LeBlanc, Eric Gaudreau, Warren G. Foster, Voleak Choeurng, William D. Fraser
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Holly N. Currie, Matthew S. Loos, Julie A. Vrana, Kristen Dragan, Jonathan W. Boyd
Self-reported smoking, serum cotinine, and blood DNA methylation
Yan Zhang, Ines Florath, Kai-Uwe Saum, Hermann Brenner
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Serum cotinine as a biomarker of tobacco exposure and the association with treatment response in early rheumatoid arthritis
Leann B. Maska, Harlan R. Sayles, James R. O'Dell, Jeffrey R. Curtis, S. Louis Bridges, Larry W. Moreland, Stacey S. Cofield, Ted R. Mikuls
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